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1
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Finn BP, Dattani MT. The molecular basis of hypoprolactinaemia. Rev Endocr Metab Disord 2024; 25:967-983. [PMID: 39417960 DOI: 10.1007/s11154-024-09906-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/02/2024] [Indexed: 10/19/2024]
Abstract
Hypoprolactinaemia is an endocrinopathy which is typically encountered as part of a combined pituitary hormone deficiency picture. The vast majority of genetic causes identified to date have been in the context of congenital hypopituitarism with multiple co-existent endocrinopathies. This is primarily with its closest hormonal relation, namely growth hormone. Acquired hypoprolactinaemia is generally rare in paediatric patients, and usually occurs together with other hormonal deficiencies. Congenital hypopituitarism occurs with an incidence of 1:4,000-10,000 cases and mutations in the following transcription factors account for the majority of documented genetic causes: PROP-1, POU1F1, LHX3/4 as well as documented case reports for a smaller subset of transcription factors and other molecules implicated in lactotroph development and prolactin secretion. Isolated prolactin deficiency has been described in a number of sporadic case reports in the literature, but no cases of mutations in the gene have been described to date. A range of genetic polymorphisms affecting multiple components of the prolactin signalling pathway have been identified in the literature, ranging from RNA spliceosome mutations (RNPC3) to loss of function mutations in IGSF-1. As paediatricians gain a greater understanding of the long-term ramifications of hypoprolactinaemia in terms of metabolic syndrome, type 2 diabetes mellitus and impaired fertility, the expectation is that clinicians will measure prolactin more frequently over time. Ultimately, we will encounter further reports of hypoprolactinaemia-related clinical presentations with further genetic mutations, in turn leading to a greater insight into the molecular basis of hypoprolactinaemia in terms of signalling pathways and downstream mediators. In the interim, the greatest untapped reserve of genetic causes remains within the phenotypic spectrum of congenital hypopituitarism.
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Affiliation(s)
- Bryan Padraig Finn
- Department of Paediatric Endocrinology, Great Ormond Street Children's Hospital, London, UK.
| | - Mehul T Dattani
- Department of Paediatric Endocrinology, Great Ormond Street Children's Hospital, London, UK
- Genetics and Genomic Medicine Research and Teaching Department, UCL GOS Institute of Child Health, London, UK
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Ventura Fernandes BH, Junqueira MS, MacRae C, Silveira de Carvalho LR. Standardizing CRISPR-Cas13 knockdown technique to investigate the role of cdh2 gene in pituitary development through growth hormone expression and transcription factors. Front Endocrinol (Lausanne) 2024; 15:1466638. [PMID: 39449741 PMCID: PMC11499105 DOI: 10.3389/fendo.2024.1466638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 09/25/2024] [Indexed: 10/26/2024] Open
Abstract
Introduction Congenital hypopituitarism (CH) is characterized by the deficiency of pituitary hormones. Among CH patients, 85% lack a molecular diagnosis. Whole Exome Sequencing (WES) identified a homozygous variant (c.865G>A, p.Val289Ile) in the CDH2 gene, responsible for N-Cadherin production, crucial for cell-cell adhesion. Predicted to be likely pathogenic, the variant was found in a patient deficient in GH, TSH, ACTH, and LH/FSH. Its impact on cell adhesion was confirmed in L1 fibroblast cell lines. Objective Create a cdh2 knockdown in zebrafish for investigating its role in pituitary development through growth hormone and transcription factors expression. Methods Utilized pET28B-RfxCas13d-His plasmid for Cas13 mRNA production via in vitro transcription, guiding Cas13 to cdh2 with three RNAs. Injected the complex into single-cell embryos for analysis up to 96 hpf. Assessed gene expression of cdh2, prop1, pit1, and gh1 using RT-qPCR. Evaluated cdh2 protein expression through the western blot technique. Results Knockdown animals displayed developmental delay. The cdh2 expression decreased by 75% within 24 hours, rebounded by 48 hours, and reached wild-type levels by 96 hpf. gh1 expression decreased at 48h but increased by 96 hpf, aligning with WT. No significant differences in prop1 and pit1 expression were observed. Conclusion Our findings underscore cdh2's role in pituitary development and hormonal regulation, offering insights for developmental biology research.
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Affiliation(s)
- Bianca Helena Ventura Fernandes
- Laboratory of Hormones and Molecular Genetics (LIM/42), Developmental Endocrinology Unit, Discipline of Endocrinology and Metabolism, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Zebrafish Facility, Technical Support Directorate for Teaching and Research, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
- Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Mara S. Junqueira
- Center for Translational Research in Oncology, Cancer Institute of the State of São Paulo, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Calum MacRae
- Department of Medicine, Harvard Medical School, Boston, MA, United States
| | - Luciani R. Silveira de Carvalho
- Laboratory of Hormones and Molecular Genetics (LIM/42), Developmental Endocrinology Unit, Discipline of Endocrinology and Metabolism, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- Zebrafish Facility, Technical Support Directorate for Teaching and Research, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
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Panigrahi M, Rajawat D, Nayak SS, Jain K, Vaidhya A, Prakash R, Sharma A, Parida S, Bhushan B, Dutt T. Genomic insights into key genes and QTLs involved in cattle reproduction. Gene 2024; 917:148465. [PMID: 38621496 DOI: 10.1016/j.gene.2024.148465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 04/05/2024] [Accepted: 04/10/2024] [Indexed: 04/17/2024]
Abstract
From an economic standpoint, reproductive characteristics are fundamental for sustainable production, particularly for monotocous livestock like cattle. A longer inter-calving interval is indicative of low reproductive capacity. This issue changes the dynamics of current and future lactations since it necessitates more inseminations, veterinary care, and hormone interventions. Various reproductive phenotypes, including ovulation, mating, fertility, pregnancy, embryonic growth, and calving-related traits, are observed in dairy cattle, and these traits have been associated with several QTLs. Calving ease, age at puberty, scrotal circumference, and inseminations per conception have been associated with 4437, 10623, 10498, and 2476 Quantitative Trait Loci (QTLs), respectively. This data offers valuable insights into enhancing and comprehending reproductive traits in livestock breeding. Studying QTLs associated with reproductive traits has far-reaching implications across various fields, from agriculture and animal husbandry to human health, evolutionary biology, and conservation. It provides the foundation for informed breeding practices, advances in biotechnology, and a deeper understanding of the genetic underpinnings of reproduction.
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Affiliation(s)
- Manjit Panigrahi
- Division of Animal Genetics, Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, UP, India.
| | - Divya Rajawat
- Division of Animal Genetics, Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, UP, India
| | - Sonali Sonejita Nayak
- Division of Animal Genetics, Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, UP, India
| | - Karan Jain
- Division of Animal Genetics, Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, UP, India
| | - Ayushi Vaidhya
- Division of Pharmacology & Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, UP, India
| | - Ravi Prakash
- Division of Pharmacology & Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, UP, India
| | - Anurodh Sharma
- Division of Animal Genetics, Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, UP, India
| | - Subhashree Parida
- Division of Pharmacology & Toxicology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, UP, India
| | - Bharat Bhushan
- Division of Animal Genetics, Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, UP, India
| | - Triveni Dutt
- Livestock Production and Management Section, Indian Veterinary Research Institute, Izatnagar, Bareilly 243122, UP, India
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Banik J, Moreira ARS, Lim J, Tomlinson S, Hardy LL, Lagasse A, Haney A, Crimmins MR, Boehm U, Odle AK, MacNicol MC, Childs GV, MacNicol AM. The Musashi RNA binding proteins direct the translational activation of key pituitary mRNAs. Sci Rep 2024; 14:5918. [PMID: 38467682 PMCID: PMC10928108 DOI: 10.1038/s41598-024-56002-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 02/29/2024] [Indexed: 03/13/2024] Open
Abstract
The pituitary functions as a master endocrine gland that secretes hormones critical for regulation of a wide variety of physiological processes including reproduction, growth, metabolism and stress responses. The distinct hormone-producing cell lineages within the pituitary display remarkable levels of cell plasticity that allow remodeling of the relative proportions of each hormone-producing cell population to meet organismal demands. The molecular mechanisms governing pituitary cell plasticity have not been fully elucidated. Our recent studies have implicated a role for the Musashi family of sequence-specific mRNA binding proteins in the control of pituitary hormone production, pituitary responses to hypothalamic stimulation and modulation of pituitary transcription factor expression in response to leptin signaling. To date, these actions of Musashi in the pituitary appear to be mediated through translational repression of the target mRNAs. Here, we report Musashi1 directs the translational activation, rather than repression, of the Prop1, Gata2 and Nr5a1 mRNAs which encode key pituitary lineage specification factors. We observe that Musashi1 further directs the translational activation of the mRNA encoding the glycolipid Neuronatin (Nnat) as determined both in mRNA reporter assays as well as in vivo. Our findings suggest a complex bifunctional role for Musashi1 in the control of pituitary cell function.
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Affiliation(s)
- Jewel Banik
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 814, Little Rock, AR, 72205, USA
| | - Ana Rita Silva Moreira
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 814, Little Rock, AR, 72205, USA
| | - Juchan Lim
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 814, Little Rock, AR, 72205, USA
| | - Sophia Tomlinson
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 814, Little Rock, AR, 72205, USA
| | - Linda L Hardy
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 814, Little Rock, AR, 72205, USA
| | - Alex Lagasse
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 814, Little Rock, AR, 72205, USA
| | - Anessa Haney
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 814, Little Rock, AR, 72205, USA
| | - Meghan R Crimmins
- Arkansas Children's Nutrition Center, Arkansas Children's Hospital, Little Rock, AR, USA
| | - Ulrich Boehm
- Department of Experimental Pharmacology, Center for Molecular Signaling, Saarland University School of Medicine, Homburg, Germany
| | - Angela K Odle
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 814, Little Rock, AR, 72205, USA
| | - Melanie C MacNicol
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 814, Little Rock, AR, 72205, USA
| | - Gwen V Childs
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 814, Little Rock, AR, 72205, USA
| | - Angus M MacNicol
- Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 814, Little Rock, AR, 72205, USA.
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Wang S, Qin Q, Jiang D, Xiao Y, Ye L, Jiang X, Guo Q. Re-analysis of gene mutations found in pituitary stalk interruption syndrome and a new hypothesis on the etiology. Front Endocrinol (Lausanne) 2024; 15:1338781. [PMID: 38464967 PMCID: PMC10920343 DOI: 10.3389/fendo.2024.1338781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 02/09/2024] [Indexed: 03/12/2024] Open
Abstract
Background Pituitary stalk interruption syndrome (PSIS) is a complex clinical syndrome characterized by varied pituitary hormone deficiencies, leading to severe manifestations across multiple systems. These include lifelong infertility, short stature, mental retardation, and potentially life-threatening pituitary crises if not promptly diagnosed and treated. Despite extensive research, the precise pathogenesis of PSIS remains unclear. Currently, there are two proposed theories regarding the pathogenic mechanisms: the genetic defect theory and the perinatal injury theory. Methods We systematically searched English databases (PubMed, Web of Science, Embase) and Chinese databases (CNKI, WanFang Med Online, Sinomed) up to February 24, 2023, to summarize studies on gene sequencing in PSIS patients. Enrichment analyses of reported mutated genes were subsequently performed using the Metascape platform. Results Our study included 37 articles. KEGG enrichment analysis revealed mutated genes were enriched in the Notch signaling pathway, Wnt signaling pathway, and Hedgehog signaling pathway. GO enrichment analysis demonstrated mutated genes were enriched in biological processes such as embryonic development, brain development, axon development and guidance, and development of other organs. Conclusion Based on our summary and analyses, we propose a new hypothesis: disruptions in normal embryonic development, partially stemming from the genetic background and/or specific gene mutations in individuals, may increase the likelihood of abnormal fetal deliveries, where different degrees of traction during delivery may lead to different levels of pituitary stalk interruption and posterior lobe ectopia. The clinical diversity observed in PSIS patients may result from a combination of genetic background, specific mutations, and variable degrees of traction during delivery.
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Affiliation(s)
- Shengjie Wang
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Qiaozhen Qin
- Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Deyue Jiang
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yan Xiao
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Lingtong Ye
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiaoxia Jiang
- Beijing Institute of Basic Medical Sciences, Beijing, China
| | - Qinghua Guo
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
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Ruggiero-Ruff RE, Le BH, Villa PA, Lainez NM, Athul SW, Das P, Ellsworth BS, Coss D. Single-Cell Transcriptomics Identifies Pituitary Gland Changes in Diet-Induced Obesity in Male Mice. Endocrinology 2024; 165:bqad196. [PMID: 38146776 PMCID: PMC10791142 DOI: 10.1210/endocr/bqad196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 12/15/2023] [Accepted: 12/22/2023] [Indexed: 12/27/2023]
Abstract
Obesity is a chronic disease with increasing prevalence worldwide. Obesity leads to an increased risk of heart disease, stroke, and diabetes, as well as endocrine alterations, reproductive disorders, changes in basal metabolism, and stress hormone production, all of which are regulated by the pituitary. In this study, we performed single-cell RNA sequencing of pituitary glands from male mice fed control and high-fat diet (HFD) to determine obesity-mediated changes in pituitary cell populations and gene expression. We determined that HFD exposure is associated with dramatic changes in somatotrope and lactotrope populations, by increasing the proportion of somatotropes and decreasing the proportion of lactotropes. Fractions of other hormone-producing cell populations remained unaffected. Gene expression changes demonstrated that in HFD, somatotropes became more metabolically active, with increased expression of genes associated with cellular respiration, and downregulation of genes and pathways associated with cholesterol biosynthesis. Despite a lack of changes in gonadotrope fraction, genes important in the regulation of gonadotropin hormone production were significantly downregulated. Corticotropes and thyrotropes were the least affected in HFD, while melanotropes exhibited reduced proportion. Lastly, we determined that changes in plasticity and gene expression were associated with changes in hormone levels. Serum prolactin was decreased corresponding to reduced lactotrope fraction, while lower luteinizing hormone and follicle-stimulating hormone in the serum corresponded to a decrease in transcription and translation. Taken together, our study highlights diet-mediated changes in pituitary gland populations and gene expression that play a role in altered hormone levels in obesity.
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Affiliation(s)
- Rebecca E Ruggiero-Ruff
- Division of Biomedical Sciences; School of Medicine, University of California, Riverside, CA 92521, USA
| | - Brandon H Le
- Institute for Integrative Genome Biology Bioinformatics Core Facility, University of California, Riverside, CA 92521, USA
| | - Pedro A Villa
- Division of Biomedical Sciences; School of Medicine, University of California, Riverside, CA 92521, USA
| | - Nancy M Lainez
- Division of Biomedical Sciences; School of Medicine, University of California, Riverside, CA 92521, USA
| | - Sandria W Athul
- Department of Physiology, School of Medicine, Southern Illinois University, Carbondale, IL 62901, USA
| | - Pratyusa Das
- Department of Physiology, School of Medicine, Southern Illinois University, Carbondale, IL 62901, USA
| | - Buffy S Ellsworth
- Department of Physiology, School of Medicine, Southern Illinois University, Carbondale, IL 62901, USA
| | - Djurdjica Coss
- Division of Biomedical Sciences; School of Medicine, University of California, Riverside, CA 92521, USA
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Poupore NS, Chidarala S, Nguyen SA, Teufel RJ, Patel KG, Pecha PP, Carroll WW. Cleft Lip and/or Palate Repair in Children With Hypopituitarism: Analysis of the Kids' Inpatient Database. Cleft Palate Craniofac J 2024; 61:94-102. [PMID: 35903934 DOI: 10.1177/10556656221117435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE Children with hypopituitarism (CwHP) can present with orofacial clefting, frequently in the setting of multiple midline anomalies. Hypopituitarism (HP) can complicate medical and surgical care; the perioperative risk in CwHP during the traditionally lower risk cleft lip and/or palate (CL/P) repair is not well described. The objective of this study is to examine the differences in complications and mortality of CL/P repair in CwHP compared to children without hypopituitarism (CwoHP). DESIGN A retrospective cross-sectional analysis. SETTING The 1997 to 2019 Kids' Inpatient Databases (KID). PATIENTS Children 3 years old and younger who underwent CL/P repair. MAIN OUTCOME MEASURE(S) Complications and mortality. RESULTS A total of 34 106 weighted cases were analyzed, with 86 having HP. CwHP had a longer length of stay (3.0 days [IQR 2.0-10.0] vs 1.0 day [IQR 1.0-2.0], P < .001) and higher rates of complications and mortality (12.8% vs 2.9%, P < .001) compared to CwoHP. Controlling for demographic factors, CwHP had 6.61 higher odds of complications and mortality than CwoHP (95% CI 3.38-12.94, P < .001). CONCLUSIONS CwHP can present with a CL/P and other midline defects that can increase the complexity of their care. These data show a significant increase in length of stay, complications, and mortality in CwHP undergoing CL/P repair. Increased multidisciplinary attention and monitoring may be needed for these children peri- and postoperatively, especially if additional comorbidities are present. Further studies on perioperative management in this population are warranted to reduce morbidity and mortality.
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Affiliation(s)
- Nicolas S Poupore
- Department of Otolaryngology - Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
- School of Medicine Greenville, University of South Carolina, Greenville, SC, USA
| | - Shreya Chidarala
- Department of Otolaryngology - Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
- College of Medicine, University of Florida, Gainesville, FL, USA
| | - Shaun A Nguyen
- Department of Otolaryngology - Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Ronald J Teufel
- Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - Krishna G Patel
- Department of Otolaryngology - Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Phayvanh P Pecha
- Department of Otolaryngology - Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - William W Carroll
- Department of Otolaryngology - Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA
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Kırkgöz T, Gürsoy S, Acar S, Nalbantoğlu Ö, Özkaya B, Anıl Korkmaz H, Hazan F, Özkan B. Genetic diagnosis of congenital hypopituitarism in Turkish patients by a target gene panel: novel pathogenic variants in GHRHR, GLI2, LHX4 and POU1F1 genes. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2023; 68:e220254. [PMID: 37948564 PMCID: PMC10916835 DOI: 10.20945/2359-4292-2022-0254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 05/02/2023] [Indexed: 11/12/2023]
Abstract
Objective Congenital hypopituitarism (CH) is a rare disease characterized by one or more hormone deficiencies of the pituitary gland. To date, many genes have been associated with CH. In this study, we identified the allelic variant spectrum of 11 causative genes in Turkish patients with CH. Materials and methods This study included 47 patients [21 girls (44.6%) and 26 boys (55.4%)] from 45 families. To identify the genetic etiology, we screened 11 candidate genes associated with CH using next-generation sequencing. To confirm and detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. Results We identified 12 possible pathogenic variants in GHRHR, GH1, GLI2, PROP-1, POU1F1, and LHX4 in 11 patients (23.4%), of which six were novel variants: two in GHRHR, two in POU1F1, one in GLI2, and one in LHX4. In all patients, these variants were most frequently found in GLI2, followed by PROP-1 and GHRHR. Conclusion Genetic causes were determined in only 23.4% of all patients with CH and 63% of molecularly diagnosed patients (7/11) from consanguineous families. Despite advances in genetics, we were unable to identify the genetic etiology of most patients with CH, suggesting the effect of unknown genes or environmental factors. More genetic studies are necessary to understand the etiology of CH.
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Affiliation(s)
- Tarık Kırkgöz
- Division of Pediatric Endocrinology, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey,
| | - Semra Gürsoy
- Division of Pediatric Genetics, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
| | - Sezer Acar
- Division of Pediatric Endocrinology, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
| | - Özlem Nalbantoğlu
- Division of Pediatric Endocrinology, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
| | - Beyhan Özkaya
- Division of Pediatric Endocrinology, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
| | - Hüseyin Anıl Korkmaz
- Division of Pediatric Endocrinology, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
| | - Filiz Hazan
- Department of Medical Genetics, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
| | - Behzat Özkan
- Division of Pediatric Endocrinology, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
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Ho KKY, Kaiser UB, Chanson P, Gadelha M, Wass J, Nieman L, Little A, Aghi MK, Raetzman L, Post K, Raverot G, Borowsky AD, Erickson D, Castaño JP, Laws ER, Zatelli MC, Sisco J, Esserman L, Yuen KCJ, Reincke M, Melmed S. Pituitary adenoma or neuroendocrine tumour: the need for an integrated prognostic classification. Nat Rev Endocrinol 2023; 19:671-678. [PMID: 37592077 DOI: 10.1038/s41574-023-00883-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/21/2023] [Indexed: 08/19/2023]
Abstract
In the 2022 fifth edition of the WHO Classification of Endocrine Tumours and of Central Nervous System Tumours, pituitary adenomas are reclassified as neuroendocrine tumours (NETs). This change confers an oncology label to neoplasms that are overwhelmingly benign. A comprehensive clinical classification schema is required to guide prognosis, therapy and outcomes for all patients with pituitary adenomas. Pituitary adenomas and NETs exhibit some morphological and ultrastructural similarities. However, unlike NETs, pituitary adenomas are highly prevalent, yet indolent and rarely become malignant. This Perspective presents the outcomes of an interdisciplinary international workshop that addressed the merit and clinical implications of the classification change of pituitary adenoma to NET. Many non-histological factors provide mechanistic insight and influence the prognosis and treatment of pituitary adenoma. We recommend the development of a comprehensive classification that integrates clinical, genetic, biochemical, radiological, pathological and molecular information for all anterior pituitary neoplasms.
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Affiliation(s)
- Ken K Y Ho
- The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
- The University of New South Wales, Sydney, New South Wales, Australia.
| | - Ursula B Kaiser
- Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Phillippe Chanson
- Université Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Monica Gadelha
- Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Lynnette Nieman
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | | | - Manish K Aghi
- University of California, San Francisco, San Francisco, CA, USA
| | - Lori Raetzman
- University of Illinois Urbana-Champaign, Urbana, IL, USA
| | - Kalmon Post
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gerald Raverot
- Hospices Civils de Lyon, Groupement Hospitalier Est, Université Claude Bernard Lyon 1, Bron, France
| | | | | | - Justo P Castaño
- Maimónides Biomedical Research Institute of Córdoba, University of Córdoba, Córdoba, Spain
- Reina Sofia University Hospital, Córdoba, Spain
| | | | | | - Jill Sisco
- The Acromegaly Community, Grove, OK, USA
| | - Laura Esserman
- University of California, San Francisco, San Francisco, CA, USA
| | - Kevin C J Yuen
- Barrow Neurological Institute, Phoenix, AZ, USA
- University of Arizona College of Medicine and Creighton School of Medicine, Phoenix, AZ, USA
| | - Martin Reincke
- Klinikum der Universität, Ludwig-Maximilians-Universität, München, Germany
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Bian Y, Hahn H, Uhmann A. The hidden hedgehog of the pituitary: hedgehog signaling in development, adulthood and disease of the hypothalamic-pituitary axis. Front Endocrinol (Lausanne) 2023; 14:1219018. [PMID: 37476499 PMCID: PMC10355329 DOI: 10.3389/fendo.2023.1219018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 06/19/2023] [Indexed: 07/22/2023] Open
Abstract
Hedgehog signaling plays pivotal roles in embryonic development, adult homeostasis and tumorigenesis. However, its engagement in the pituitary gland has been long underestimated although Hedgehog signaling and pituitary embryogenic development are closely linked. Thus, deregulation of this signaling pathway during pituitary development results in malformation of the gland. Research of the last years further implicates a regulatory role of Hedgehog signaling in the function of the adult pituitary, because its activity is also interlinked with homeostasis, hormone production, and most likely also formation of neoplasms of the gland. The fact that this pathway can be efficiently targeted by validated therapeutic strategies makes it a promising candidate for treating pituitary diseases. We here summarize the current knowledge about the importance of Hedgehog signaling during pituitary development and review recent data that highlight the impact of Hedgehog signaling in the healthy and the diseased adult pituitary gland.
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11
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Moalla M, Mnif-Feki M, Safi W, Charfi N, Mejdoub-Rekik N, Abid M, Hadj Kacem F, Hadj Kacem H. Analysis of ProP1 Gene in a Cohort of Tunisian Patients with Congenital Combined Pituitary Hormone Deficiency. J Clin Med 2022; 11:7525. [PMID: 36556141 PMCID: PMC9787973 DOI: 10.3390/jcm11247525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/07/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Background: Non-syndromic combined pituitary hormone deficiency (CPHD) occurs due to defects in transcription factors that govern early pituitary development and the specification of hormone-producing cells. The most common mutations are in the Prophet of Pit-1 (ProP1) gene. This work aims to (1) report findings of genetic analyses of Tunisian patients with non-syndromic CPHD and (2) describe their phenotype patterns and their evolution through life. Methods: Fifteen patients from twelve unrelated families with variable clinical phenotypes were included after excluding autoimmune and acquired forms of non-syndromic CPHD. Detailed pedigree charts and auxological, hormonal, radiological, and therapeutic details were recorded. Sanger sequencing was performed, and sequences were analyzed with a specific focus on coding and splice site regions of the ProP1 gene. Retained variants were classified using several in silico pathogenicity prediction tools and the VarSome platform. Results: We identified the common p.Arg73Cys mutation in seven patients from four unrelated pedigrees. We found a novel homozygous mutation (c.340C>T) in one sporadic case. This mutation generates a truncated ProP1 protein, predicted to be non-functional, lacking the last 112 codons (p.(Gln114Ter)). We confirmed by polymerase chain reaction (PCR) the absence of large exon deletions or insertions in the remaining sporadic patients (7/8). Conclusions: We report two mutations {one newly identified [p.(Gln114Ter)] and one previously reported (p.Arg73Cys)} in five unrelated Tunisian families with non-syndromic CPHD. This work is of clinical importance as it reports the high frequency of the p.Arg73Cys mutation in Tunisian CPHD families. Our study also illuminated the involvement of novel gene(s) in the emergence of non-syndromic CPHD.
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Affiliation(s)
- Mariam Moalla
- Laboratory of Molecular and Cellular Screening Processes, Center of Biotechnology of Sfax, Sfax 3018, Tunisia
- Laboratory of Human Molecular Genetics, Faculty of Medicine of Sfax, University of Sfax, Sfax 3029, Tunisia
| | - Mouna Mnif-Feki
- Endocrinology Department, Hedi Chaker Hospital, Sfax 3029, Tunisia
| | - Wajdi Safi
- Endocrinology Department, Hedi Chaker Hospital, Sfax 3029, Tunisia
| | - Nadia Charfi
- Endocrinology Department, Hedi Chaker Hospital, Sfax 3029, Tunisia
| | | | - Mohamed Abid
- Endocrinology Department, Hedi Chaker Hospital, Sfax 3029, Tunisia
| | - Faten Hadj Kacem
- Endocrinology Department, Hedi Chaker Hospital, Sfax 3029, Tunisia
| | - Hassen Hadj Kacem
- Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah P.O. Box 27272, United Arab Emirates
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12
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Smith OE, Roussel V, Morin F, Ongaro L, Zhou X, Bertucci MC, Bernard DJ, Murphy BD. Steroidogenic Factor 1 Regulation of the Hypothalamic-Pituitary-Ovarian Axis of Adult Female Mice. Endocrinology 2022; 163:6542939. [PMID: 35247045 PMCID: PMC8974829 DOI: 10.1210/endocr/bqac028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Indexed: 11/19/2022]
Abstract
The orphan nuclear receptor steroidogenic factor-1 (SF-1 or NR5A1) is an indispensable regulator of adrenal and gonadal formation, playing roles in sex determination, hypothalamic development, and pituitary function. This study aimed to identify the roles of SF-1 in postnatal female reproductive function. Using a progesterone receptor-driven Cre recombinase, we developed a novel murine model, characterized by conditional depletion of SF-1 [PR-Cre;Nr5a1f/f; conditional knockout (cKO)] in the hypothalamic-pituitary-gonadal axis. Mature female cKO were infertile due to the absence of ovulation. Reduced gonadotropin concentrations in the pituitary gland that were nevertheless sufficient to maintain regular estrous cycles were observed in mature cKO females. The cKO ovaries showed abnormal lipid accumulation in the stroma, associated with an irregular expression of cholesterol homeostatic genes such as Star, Scp2, and Acat1. The depletion of SF-1 in granulosa cells prevented appropriate cumulus oöphorus expansion, characterized by reduced expression of Areg, Ereg, and Ptgs2. Exogenous delivery of gonadotropins to cKO females to induce ovulation did not restore fertility and was associated with impaired formation and function of corpora lutea accompanied by reduced expression of the steroidogenic genes Cyp11a1 and Cyp19a1 and attenuated progesterone production. Surgical transplantation of cKO ovaries to ovariectomized control animals (Nr5a1f/f) resulted in 2 separate phenotypes, either sterility or apparently normal fertility. The deletion of SF-1 in the pituitary and in granulosa cells near the moment of ovulation demonstrated that this nuclear receptor functions across the pituitary-gonadal axis and plays essential roles in gonadotropin synthesis, cumulus expansion, and luteinization.
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Affiliation(s)
- Olivia E Smith
- Centre de recherche en reproduction et fertilité (CRRF), Université de Montréal, Saint Hyacinthe, Québec, Canada
| | - Vickie Roussel
- Centre de recherche en reproduction et fertilité (CRRF), Université de Montréal, Saint Hyacinthe, Québec, Canada
| | - Fanny Morin
- Centre de recherche en reproduction et fertilité (CRRF), Université de Montréal, Saint Hyacinthe, Québec, Canada
| | - Luisina Ongaro
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Xiang Zhou
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Micka C Bertucci
- School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia
| | - Daniel J Bernard
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
| | - Bruce D Murphy
- Centre de recherche en reproduction et fertilité (CRRF), Université de Montréal, Saint Hyacinthe, Québec, Canada
- Correspondence: Bruce D. Murphy, PhD, Centre de Recherche en Reproduction et Fertilité, Université de Montréal, Saint-Hyacinthe, Québec, J2S 7C6, Canada. E-mail:
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Swee DS, Quinton R. Current concepts surrounding neonatal hormone therapy for boys with congenital hypogonadotropic hypogonadism. Expert Rev Endocrinol Metab 2022; 17:47-61. [PMID: 34994276 DOI: 10.1080/17446651.2022.2023008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 12/22/2021] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Congenital hypogonadotropic hypogonadism (CHH) is a genetic disorder of reproduction and development, characterized by deficient gonadotropin-releasing hormone (GnRH) secretion or action, affecting 1-in-4,000-15,000 males. Micropenis and undescended testes are cardinal features of antenatal GnRH deficiency and could indicate absent minipuberty in the first postnatal months. In this review, we outline the pathophysiology and clinical consequences of absent minipuberty and its implications for optimal approaches to the endocrine management of affected boys. AREAS COVERED Deficient GnRH activity during fetal development and neonatal-infancy phase of minipuberty accounts for the diminished mass of Sertoli cells and seminiferous tubules among CHH males, enduring impairment of reproductive function even during gonadotropin replacement in adult life. In overcoming this obstacle, several clinical studies of neonatal gonadotropin replacement have consistently shown positive results in inducing testicular development and correcting cryptorchidism. EXPERT OPINION A high index of clinical suspicion, combined with hormonal testing undertaken in the postnatal period of 1-4 months, can reliably confirm or refute the diagnosis of CHH. Timely identification of CHH in affected male infants (having characteristic "red flag' developmental anomalies) opens up the possibility for gonadotropin replacement as a targeted therapy to restore the normal hormonal milieu of minipuberty. Further work is necessary in formulating optimal gonadotropin treatment regimens to be more widely adopted in clinical practice.
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Affiliation(s)
- Du Soon Swee
- Department of Endocrinology, Singapore General Hospital, Singapore, Singapore
| | - Richard Quinton
- Department of Endocrinology, Diabetes & Metabolism Royal Victoria Infirmary, Newcastle-Upon-Tyne Hospitals, Newcastle-upon-Tyne, UK
- Translational & Clinical Research Institute, University of Newcastle-upon-Tyne, Newcastle-Upon-Tyne, UK
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14
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Bando H, Gergics P, Bohnsack BL, Toolan KP, Richter CE, Shavit JA, Camper SA. Otx2b mutant zebrafish have pituitary, eye and mandible defects that model mammalian disease. Hum Mol Genet 2021; 29:1648-1657. [PMID: 32277752 DOI: 10.1093/hmg/ddaa064] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/29/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023] Open
Abstract
Combined pituitary hormone deficiency (CPHD) is a genetically heterogeneous disorder caused by mutations in over 30 genes. The loss-of-function mutations in many of these genes, including orthodenticle homeobox 2 (OTX2), can present with a broad range of clinical symptoms, which provides a challenge for predicting phenotype from genotype. Another challenge in human genetics is functional evaluation of rare genetic variants that are predicted to be deleterious. Zebrafish are an excellent vertebrate model for evaluating gene function and disease pathogenesis, especially because large numbers of progeny can be obtained, overcoming the challenge of individual variation. To clarify the utility of zebrafish for the analysis of CPHD-related genes, we analyzed the effect of OTX2 loss of function in zebrafish. The otx2b gene is expressed in the developing hypothalamus, and otx2bhu3625/hu3625 fish exhibit multiple defects in the development of head structures and are not viable past 10 days post fertilization (dpf). Otx2bhu3625/hu3625 fish have a small hypothalamus and low expression of pituitary growth hormone and prolactin (prl). The gills of otx2bhu3625/hu3625 fish have weak sodium influx, consistent with the role of prolactin in osmoregulation. The otx2bhu3625/hu3625 eyes are microphthalmic with colobomas, which may underlie the inability of the mutant fish to find food. The small pituitary and eyes are associated with reduced cell proliferation and increased apoptosis evident at 3 and 5 dpf, respectively. These observations establish the zebrafish as a useful tool for the analysis of CPHD genes with variable and complex phenotypes.
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Affiliation(s)
- Hironori Bando
- Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Peter Gergics
- Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Brenda L Bohnsack
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kevin P Toolan
- Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Catherine E Richter
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jordan A Shavit
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Sally A Camper
- Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
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15
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Obara-Moszyńska M, Budny B, Kałużna M, Zawadzka K, Jamsheer A, Rohde A, Ruchała M, Ziemnicka K, Niedziela M. CDON gene contributes to pituitary stalk interruption syndrome associated with unilateral facial and abducens nerve palsy. J Appl Genet 2021; 62:621-629. [PMID: 34235642 PMCID: PMC8571149 DOI: 10.1007/s13353-021-00649-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 06/21/2021] [Accepted: 06/28/2021] [Indexed: 11/06/2022]
Abstract
The relationship between congenital defects of the brain and facial anomalies was proven. The Hedgehog signaling pathway plays a fundamental role in normal craniofacial development in humans. Mutations in the sonic hedgehog (SHH) signaling gene CDON have been recently reported in patients with holoprosencephaly and with pituitary stalk interruption syndrome (PSIS). This study’s aim was an elucidation of an 18-year-old patient presenting PSIS, multiple pituitary hormone deficiency, and congenital unilateral facial and abducens nerve palsy. Additionally, bilateral sensorineural hearing loss, dominating at the right site, was diagnosed. From the second year of life, growth deceleration was observed, and from the age of eight, anterior pituitary hormone deficiencies were gradually confirmed and substituted. At the MRI, characteristic triad for PSIS (anterior pituitary hypoplasia, interrupted pituitary stalk and ectopic posterior lobe) was diagnosed. We performed a comprehensive genomic screening, including microarrays for structural rearrangements and whole-exome sequencing for a monogenic defect. A novel heterozygous missense variant in the CDON gene (c.1814G > T; p.Gly605Val) was identified. The variant was inherited from the mother, who, besides short stature, did not show any disease symptoms. The variant was absent in control databases and 100 healthy subjects originating from the same population. We report a novel variant in the CDON gene associated with PSIS and congenital cranial nerve palsy. The variant revealed autosomal dominant inheritance with incomplete penetrance in concordance with previous studies reporting CDON defects.
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Affiliation(s)
- Monika Obara-Moszyńska
- Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, 27/33 Szpitalna Str, 60-572, Poznan, Poland.
| | - Bartłomiej Budny
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland
| | - Małgorzata Kałużna
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland
| | - Katarzyna Zawadzka
- MNM Diagnostics Sp. z o.o., 64 Macieja Rataja Str., 61-695, Poznan, Poland
| | - Aleksander Jamsheer
- Department of Medical Genetics, Poznan University of Medical Sciences, 8 Rokietnicka Str, 60-806, Poznan, Poland
| | - Anna Rohde
- Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, 27/33 Szpitalna Str, 60-572, Poznan, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland
| | - Katarzyna Ziemnicka
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 49 Przybyszewskiego Str., 60-355, Poznan, Poland
| | - Marek Niedziela
- Department of Pediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences, 27/33 Szpitalna Str, 60-572, Poznan, Poland
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16
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Daly AZ, Mortensen AH, Bando H, Camper SA. Pituitary Tumors and Immortalized Cell Lines Generated by Cre-Inducible Expression of SV40 T Antigen. Endocrinology 2021; 162:6219492. [PMID: 33837405 PMCID: PMC8183496 DOI: 10.1210/endocr/bqab073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Indexed: 02/07/2023]
Abstract
Targeted oncogenesis is the process of driving tumor formation by engineering transgenic mice that express an oncogene under the control of a cell-type specific promoter. Such tumors can be adapted to cell culture, providing immortalized cell lines. To make it feasible to follow the process of tumorigenesis and increase the opportunity for generating cell lines, we developed a mouse strain that expresses SV40 T antigens in response to Cre-recombinase. Using CRISPR/Cas9 we inserted a cassette with coding sequences for SV40 T antigens and an internal ribosome entry site with green fluorescent protein cassette (IRES-GFP) into the Rosa26 locus, downstream from a stop sequence flanked by loxP sites: Rosa26LSL-SV40-GFP. These mice were mated with previously established Prop1-cre and Tshb-cre transgenic lines. Both the Rosa26LSL-SV40-GFP/+; Prop1-cre and Rosa26LSL-SV40-GFP/+; Tshb-cre mice developed fully penetrant dwarfism and large tumors by 4 weeks. Tumors from both of these mouse lines were adapted to growth in cell culture. We have established a progenitor-like cell line (PIT-P1) that expresses Sox2 and Pitx1, and a thyrotrope-like cell line (PIT-T1) that expresses Pou1f1 and Cga. These studies demonstrate the utility of the novel, Rosa26LSL-SV40-GFP mouse line for reliable targeted oncogenesis and development of unique cell lines.
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Affiliation(s)
| | | | - Hironori Bando
- University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Sally A Camper
- University of Michigan Medical School, Ann Arbor, MI 48109, USA
- Correspondence: Sally A. Camper, Ph.D., 5704 Medical Science Building II, 1301 Catherine St, Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
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17
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Nadaf J, de Kock L, Chong AS, Korbonits M, Thorner P, Benlimame N, Fu L, Peet A, Warner J, Ploner O, Shuangshoti S, Albrecht S, Hamel N, Priest JR, Rivera B, Ragoussis J, Foulkes WD. Molecular characterization of DICER1-mutated pituitary blastoma. Acta Neuropathol 2021; 141:929-944. [PMID: 33644822 DOI: 10.1007/s00401-021-02283-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 02/08/2021] [Accepted: 02/09/2021] [Indexed: 12/13/2022]
Abstract
Pituitary blastoma (PitB) has recently been identified as a rare and potentially lethal pediatric intracranial tumor. All cases that have been studied molecularly possess at least one DICER1 pathogenic variant. Here, we characterized nine pituitary samples, including three fresh frozen PitBs, three normal fetal pituitary glands and three normal postnatal pituitary glands using small-RNA-Seq, RNA-Seq, methylation profiling, whole genome sequencing and Nanostring® miRNA analyses; an extended series of 21 pituitary samples was used for validation purposes. These analyses demonstrated that DICER1 RNase IIIb hotspot mutations in PitBs induced improper processing of miRNA precursors, resulting in aberrant 5p-derived miRNA products and a skewed distribution of miRNAs favoring mature 3p over 5p miRNAs. This led to dysregulation of hundreds of 5p and 3p miRNAs and concomitant dysregulation of numerous mRNA targets. Gene expression analysis revealed PRAME as the most significantly upregulated gene (500-fold increase). PRAME is a member of the Retinoic Acid Receptor (RAR) signaling pathway and in PitBs, the RAR, WNT and NOTCH pathways are dysregulated. Cancer Hallmarks analysis showed that PI3K pathway is activated in the tumors. Whole genome sequencing demonstrated a quiet genome with very few somatic alterations. The comparison of methylation profiles to publicly available data from ~ 3000 other central nervous system tumors revealed that PitBs have a distinct methylation profile compared to all other tumors, including pituitary adenomas. In conclusion, this comprehensive characterization of DICER1-related PitB revealed key molecular underpinnings of PitB and identified pathways that could potentially be exploited in the treatment of this tumor.
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Affiliation(s)
- Javad Nadaf
- Department of Medical Genetics, The Lady Davis Institute, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, QC, H3T 1E2, Canada
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- McGill University Genome Centre, Montreal, QC, Canada
| | - Leanne de Kock
- Department of Medical Genetics, The Lady Davis Institute, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, QC, H3T 1E2, Canada
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
| | - Anne-Sophie Chong
- Department of Medical Genetics, The Lady Davis Institute, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, QC, H3T 1E2, Canada
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Márta Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Paul Thorner
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Naciba Benlimame
- Research Pathology Facility, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada
| | - Lili Fu
- Department of Pathology, McGill University Health Centre, Montreal, QC, Canada
| | - Andrew Peet
- Birmingham Children's NHS Foundation Trust, Birmingham, UK
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Justin Warner
- Department of Child Health, University Hospital of Wales, Heath Park, Cardiff, UK
| | | | - Shanop Shuangshoti
- Department of Pathology and Chulalongkorn GenePRO Center, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Steffen Albrecht
- Department of Pathology, McGill University Health Centre, Montreal, QC, Canada
| | - Nancy Hamel
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | | | - Barbara Rivera
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada
| | - Jiannis Ragoussis
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- McGill University Genome Centre, Montreal, QC, Canada
| | - William D Foulkes
- Department of Medical Genetics, The Lady Davis Institute, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, QC, H3T 1E2, Canada.
- Department of Human Genetics, McGill University, Montreal, QC, Canada.
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
- Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada.
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Bosch i Ara L, Katugampola H, Dattani MT. Congenital Hypopituitarism During the Neonatal Period: Epidemiology, Pathogenesis, Therapeutic Options, and Outcome. Front Pediatr 2021; 8:600962. [PMID: 33634051 PMCID: PMC7902025 DOI: 10.3389/fped.2020.600962] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 12/31/2020] [Indexed: 12/13/2022] Open
Abstract
Introduction: Congenital hypopituitarism (CH) is characterized by a deficiency of one or more pituitary hormones. The pituitary gland is a central regulator of growth, metabolism, and reproduction. The anterior pituitary produces and secretes growth hormone (GH), adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and prolactin. The posterior pituitary hormone secretes antidiuretic hormone and oxytocin. Epidemiology: The incidence is 1 in 4,000-1 in 10,000. The majority of CH cases are sporadic; however, a small number of familial cases have been identified. In the latter, a molecular basis has frequently been identified. Between 80-90% of CH cases remain unsolved in terms of molecular genetics. Pathogenesis: Several transcription factors and signaling molecules are involved in the development of the pituitary gland. Mutations in any of these genes may result in CH including HESX1, PROP1, POU1F1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, GLI2, and FGF8. Over the last 5 years, several novel genes have been identified in association with CH, but it is likely that many genes remain to be identified, as the majority of patients with CH do not have an identified mutation. Clinical manifestations: Genotype-phenotype correlations are difficult to establish. There is a high phenotypic variability associated with different genetic mutations. The clinical spectrum includes severe midline developmental disorders, hypopituitarism (in isolation or combined with other congenital abnormalities), and isolated hormone deficiencies. Diagnosis and treatment: Key investigations include MRI and baseline and dynamic pituitary function tests. However, dynamic tests of GH secretion cannot be performed in the neonatal period, and a diagnosis of GH deficiency may be based on auxology, MRI findings, and low growth factor concentrations. Once a hormone deficit is confirmed, hormone replacement should be started. If onset is acute with hypoglycaemia, cortisol deficiency should be excluded, and if identified this should be rapidly treated, as should TSH deficiency. This review aims to give an overview of CH including management of this complex condition.
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Affiliation(s)
- Laura Bosch i Ara
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, United Kingdom
| | - Harshini Katugampola
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, United Kingdom
| | - Mehul T. Dattani
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, United Kingdom
- Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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19
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Wu ZY, Li YL, Chang B. Pituitary stalk interruption syndrome and liver changes: From clinical features to mechanisms. World J Gastroenterol 2020; 26:6909-6922. [PMID: 33311939 PMCID: PMC7701950 DOI: 10.3748/wjg.v26.i44.6909] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/14/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
Pituitary stalk interruption syndrome (PSIS) is a rare congenital abnormality characterized by thinning or disappearance of the pituitary stalk, hypoplasia of the anterior pituitary and an ectopic posterior pituitary. Although the etiology of PSIS is still unclear, gene changes and perinatal adverse events such as breech delivery may play important roles in the pathogenesis of PSIS. PSIS can cause multiple hormone deficiencies, such as growth hormone, which then cause a series of changes in the human body. On the one hand, hormone changes affect growth and development, and on the other hand, they could affect human metabolism and subsequently the liver resulting in nonalcoholic fatty liver disease (NAFLD). Under the synergistic effect of multiple mechanisms, the progression of NAFLD caused by PSIS is faster than that due to other causes. Therefore, in addition to early identification of PSIS, timely hormone replacement therapy and monitoring of relevant hormone levels, clinicians should routinely assess the liver function while managing PSIS.
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Affiliation(s)
- Ze-Yu Wu
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Yi-Ling Li
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bing Chang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Budny B, Karmelita-Katulska K, Stajgis M, Żemojtel T, Ruchała M, Ziemnicka K. Copy Number Variants Contributing to Combined Pituitary Hormone Deficiency. Int J Mol Sci 2020; 21:ijms21165757. [PMID: 32796691 PMCID: PMC7461210 DOI: 10.3390/ijms21165757] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/07/2020] [Accepted: 08/08/2020] [Indexed: 12/25/2022] Open
Abstract
Combined pituitary hormone deficiency represents a disorder with complex etiology. For many patients, causes of the disease remain unexplained, despite usage of advanced genetic testing. Although major and common transcription factors were identified two decades ago, we still struggle with identification of rare inborn factors contributing to pituitary function. In this report, we follow up genomic screening of CPHD patient cohort that were previously tested for changes in a coding sequences of genes with the use of the whole exome. We aimed to find contribution of rare copy number variations (CNVs). As a result, we identified genomic imbalances in 7 regions among 12 CPHD patients. Five out of seven regions showed copy gains whereas two presented losses of genomic fragment. Three regions with detected gains encompassed known CPHD genes namely LHX4, HESX1, and OTX2. Among new CPHD loci, the most interesting seem to be the region covering SIX3 gene, that is abundantly expressed in developing brain, and together with HESX1 contributes to pituitary organogenesis as it was evidenced before in functional studies. In conclusion, with the use of broadened genomic approach we identified copy number imbalances for 12 CPHD patients. Although further functional studies are required in order to estimate its true impact on expression pattern during pituitary organogenesis and CPHD etiology.
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Affiliation(s)
- Bartłomiej Budny
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (M.R.); (K.Z.)
- Correspondence: ; Tel.: +48-691-814-330
| | - Katarzyna Karmelita-Katulska
- Department of General Radiology and Neuroradiology, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (K.K.-K.); (M.S.)
| | - Marek Stajgis
- Department of General Radiology and Neuroradiology, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (K.K.-K.); (M.S.)
| | - Tomasz Żemojtel
- Genomics Platform, Berlin Institute of Health, 10117 Berlin, Germany;
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, 60-569 Poznan, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (M.R.); (K.Z.)
| | - Katarzyna Ziemnicka
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, 60-355 Poznan, Poland; (M.R.); (K.Z.)
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21
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Abstract
The development of the anterior pituitary gland occurs in distinct sequential developmental steps, leading to the formation of a complex organ containing five different cell types secreting six different hormones. During this process, the temporal and spatial expression of a cascade of signaling molecules and transcription factors plays a crucial role in organ commitment, cell proliferation, patterning, and terminal differentiation. The morphogenesis of the gland and the emergence of distinct cell types from a common primordium are governed by complex regulatory networks involving transcription factors and signaling molecules that may be either intrinsic to the developing pituitary or extrinsic, originating from the ventral diencephalon, the oral ectoderm, and the surrounding mesenchyme. Endocrine cells of the pituitary gland are organized into structural and functional networks that contribute to the coordinated response of endocrine cells to stimuli; these cellular networks are formed during embryonic development and are maintained or may be modified in adulthood, contributing to the plasticity of the gland. Abnormalities in any of the steps of pituitary development may lead to congenital hypopituitarism that includes a spectrum of disorders from isolated to combined hormone deficiencies including syndromic disorders such as septo-optic dysplasia. Over the past decade, the acceleration of next-generation sequencing has allowed for rapid analysis of the patient genome to identify novel mutations and novel candidate genes associated with hypothalmo-pituitary development. Subsequent functional analysis using patient fibroblast cells, and the generation of stem cells derived from patient cells, is fast replacing the need for animal models while providing a more physiologically relevant characterization of novel mutations. Furthermore, CRISPR-Cas9 as the method for gene editing is replacing previous laborious and time-consuming gene editing methods that were commonly used, thus yielding knockout cell lines in a fraction of the time. © 2020 American Physiological Society. Compr Physiol 10:389-413, 2020.
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Affiliation(s)
- Kyriaki S Alatzoglou
- Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, University College London (UCL), London, UK
| | - Louise C Gregory
- Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, University College London (UCL), London, UK
| | - Mehul T Dattani
- Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, University College London (UCL), London, UK
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22
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Vineeth MR, Gupta ID, Verma A, Kumari S. Identification of SNPs in coding sequence of PROP1 gene and their association with bull fertility in Sahiwal cattle. BIOL RHYTHM RES 2019. [DOI: 10.1080/09291016.2019.1629092] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- M. R. Vineeth
- Molecular Genetics Lab, Animal Genetics and Breeding Division, ICAR-NDRI, Karnal, India
| | - I. D. Gupta
- Molecular Genetics Lab, Animal Genetics and Breeding Division, ICAR-NDRI, Karnal, India
| | - Archana Verma
- Molecular Genetics Lab, Animal Genetics and Breeding Division, ICAR-NDRI, Karnal, India
| | - Santosh Kumari
- Molecular Genetics Lab, Animal Genetics and Breeding Division, ICAR-NDRI, Karnal, India
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23
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Srikanth K, Kim NY, Park W, Kim JM, Kim KD, Lee KT, Son JH, Chai HH, Choi JW, Jang GW, Kim H, Ryu YC, Nam JW, Park JE, Kim JM, Lim D. Comprehensive genome and transcriptome analyses reveal genetic relationship, selection signature, and transcriptome landscape of small-sized Korean native Jeju horse. Sci Rep 2019; 9:16672. [PMID: 31723199 PMCID: PMC6853925 DOI: 10.1038/s41598-019-53102-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 10/18/2019] [Indexed: 12/16/2022] Open
Abstract
The Jeju horse, indigenous to the Jeju Island in Korea may have originated from Mongolian horses. Adaptations to the local harsh environment have conferred Jeju horse with unique traits such as small-sized body, stocky head, and shorter limbs. These characteristics have not been studied previously at the genomic level. Therefore, we sequenced and compared the genome of 41 horses belonging to 6 breeds. We identified numerous breed-specific non-synonymous SNPs and loss-of-function mutants. Demographic and admixture analyses showed that, though Jeju horse is genetically the closest to the Mongolian breeds, its genetic ancestry is independent of that of the Mongolian breeds. Genome wide selection signature analysis revealed that genes such as LCORL, MSTN, HMGA2, ZFAT, LASP1, PDK4, and ACTN2, were positively selected in the Jeju horse. RNAseq analysis showed that several of these genes were also differentially expressed in Jeju horse compared to Thoroughbred horse. Comparative muscle fiber analysis showed that, the type I muscle fibre content was substantially higher in Jeju horse compared to Thoroughbred horse. Our results provide insights about the selection of complex phenotypic traits in the small-sized Jeju horse and the novel SNPs identified will aid in designing high-density SNP chip for studying other native horse breeds.
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Affiliation(s)
- Krishnamoorthy Srikanth
- Animal Genomics and Bioinformatics Division, National Institute of Animal Science, Rural Development Administration, Wanju, 55365, Republic of Korea
| | - Nam-Young Kim
- Subtropical Livestock Research Institute, National Institute of Animal Science, Rural Development Administration, Jeju-do, 63242, Republic of Korea
| | - WonCheoul Park
- Animal Genomics and Bioinformatics Division, National Institute of Animal Science, Rural Development Administration, Wanju, 55365, Republic of Korea
| | - Jae-Min Kim
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | | | - Kyung-Tai Lee
- Animal Breeding and Genetics Division, National Institute of Animal Science, Rural Development Administration, Wanju, 55365, Republic of Korea
| | - Ju-Hwan Son
- Animal Genomics and Bioinformatics Division, National Institute of Animal Science, Rural Development Administration, Wanju, 55365, Republic of Korea
| | - Han-Ha Chai
- Animal Genomics and Bioinformatics Division, National Institute of Animal Science, Rural Development Administration, Wanju, 55365, Republic of Korea
| | - Jung-Woo Choi
- College of Animal Life Science, Kangwon National University, Chuncheon, 24341, Republic of Korea
| | - Gul-Won Jang
- Animal Genomics and Bioinformatics Division, National Institute of Animal Science, Rural Development Administration, Wanju, 55365, Republic of Korea
| | | | - Youn-Chul Ryu
- Division of Biotechnology, Jeju National University, Jeju, 63243, Republic of Korea
| | - Jin-Wu Nam
- Department of Life Science, Hanyang University, Seoul, 133-791, Republic of Korea
| | - Jong-Eun Park
- Animal Genomics and Bioinformatics Division, National Institute of Animal Science, Rural Development Administration, Wanju, 55365, Republic of Korea
| | - Jun-Mo Kim
- Department of Animal Science and Technology, College of Biotechnology and Natural Resources, Chung-Ang University, Ansung-si, 17546, Republic of Korea.
| | - Dajeong Lim
- Animal Genomics and Bioinformatics Division, National Institute of Animal Science, Rural Development Administration, Wanju, 55365, Republic of Korea.
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24
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The Homeodomain Transcription Factors Vax1 and Six6 Are Required for SCN Development and Function. Mol Neurobiol 2019; 57:1217-1232. [PMID: 31705443 DOI: 10.1007/s12035-019-01781-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 09/12/2019] [Indexed: 12/13/2022]
Abstract
The brain's primary circadian pacemaker, the suprachiasmatic nucleus (SCN), is required to translate day-length and circadian rhythms into neuronal, hormonal, and behavioral rhythms. Here, we identify the homeodomain transcription factor ventral anterior homeobox 1 (Vax1) as required for SCN development, vasoactive intestinal peptide expression, and SCN output. Previous work has shown that VAX1 is required for gonadotropin-releasing hormone (GnRH/LHRH) neuron development, a neuronal population controlling reproductive status. Surprisingly, the ectopic expression of a Gnrh-Cre allele (Gnrhcre) in the SCN confirmed the requirement of both VAX1 (Vax1flox/flox:Gnrhcre, Vax1Gnrh-cre) and sine oculis homeobox protein 6 (Six6flox/flox:Gnrhcre, Six6Gnrh-cre) in SCN function in adulthood. To dissociate the role of Vax1 and Six6 in GnRH neuron and SCN function, we used another Gnrh-cre allele that targets GnRH neurons, but not the SCN (Lhrhcre). Both Six6Lhrh-cre and Vax1Lhrh-cre were infertile, and in contrast to Vax1Gnrh-cre and Six6Gnrh-cre mice, Six6Lhrh-cre and Vax1Lhrh-cre had normal circadian behavior. Unexpectedly, ~ 1/4 of the Six6Gnrh-cre mice were unable to entrain to light, showing that ectopic expression of Gnrhcre impaired function of the retino-hypothalamic tract that relays light information to the brain. This study identifies VAX1, and confirms SIX6, as transcription factors required for SCN development and function and demonstrates the importance of understanding how ectopic CRE expression can impact the results.
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25
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Correa FA, Nakaguma M, Madeira JLO, Nishi MY, Abrão MG, Jorge AAL, Carvalho LR, Arnhold IJP, Mendonça BB. Combined pituitary hormone deficiency caused by PROP1 mutations: update 20 years post-discovery. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2019; 63:167-174. [PMID: 31090814 PMCID: PMC10522137 DOI: 10.20945/2359-3997000000139] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 03/12/2019] [Indexed: 11/23/2022]
Abstract
The first description of patients with combined pituitary hormone deficiencies (CPHD) caused by PROP1 mutations was made 20 years ago. Here we updated the clinical and genetic characteristics of patients with PROP1 mutations and summarized the phenotypes of 14 patients with 7 different pathogenic PROP1 mutations followed at the Hospital das Clínicas of the University of Sao Paulo. In addition to deficiencies in GH, TSH, PRL and gonadotropins some patients develop late ACTH deficiency. Therefore, patients with PROP1 mutations require permanent surveillance. On magnetic resonance imaging, the pituitary stalk is normal, and the posterior lobe is in the normal position. The anterior lobe in patients with PROP1 mutations is usually hypoplastic but may be normal or even enlarged. Bi-allelic PROP1 mutations are currently the most frequently recognized genetic cause of CPHD worldwide. PROP1 defects occur more frequently among offspring of consanguineous parents and familial cases, but they also occur in sporadic cases, especially in countries in which the prevalence of PROP1 mutations is relatively high. We classified all reported PROP1 variants described to date according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines: 29 were pathogenic, 2 were likely pathogenic, and 2 were of unknown significance. An expansion of the phenotype of patients with PROP1 mutations was observed since the first description 20 years ago: variable anterior pituitary size, different pathogenic mutations, and late development of ACTH deficiency. PROP1 mutations are the most common cause of autosomal recessive CPHD with a topic posterior pituitary lobe. Arch Endocrinol Metab. 2019;63(2):167-74.
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Affiliation(s)
- Fernanda A Correa
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Marilena Nakaguma
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - João L O Madeira
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Mirian Y Nishi
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Milena G Abrão
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Alexander A L Jorge
- Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Luciani R Carvalho
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Ivo J P Arnhold
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Berenice B Mendonça
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
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26
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Montenegro YHA, de Queiroga Nascimento D, de Assis TO, Santos-Lopes SSD. The epigenetics of the hypothalamic-pituitary-adrenal axis in fetal development. Ann Hum Genet 2019; 83:195-213. [PMID: 30843189 DOI: 10.1111/ahg.12306] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 02/13/2019] [Accepted: 02/14/2019] [Indexed: 01/16/2023]
Abstract
The hypothalamic-pituitary-adrenal (HPA) axis is an important hormonal mechanism of the human body and is extremely programmable during embryonic and fetal development. Analyzing its development in this period is the key to understanding in fact how vulnerabilities of congenital diseases occur and any other changes in the phenotypic and histophysiological aspects of the fetus. The environment in which the mother is exposed during the gestational period can influence this axis. Knowing this, our objective was to analyze in recent research the possible impact of epigenetic programming on the HPA axis and its consequences for fetal development. This review brought together articles from two databases: ScienceDirect and PUBMED researched based on key words such as "epigenetics, HPA axis, cardiovascular disease, and circulatory problems" where it demonstrated full relevance in experimental and scientific settings. A total of 101 articles were selected following the criteria established by the researchers. Thus, it was possible to verify that the development of the HPA axis is directly related to changes that occur in the cardiovascular system, to the cerebral growth and other systems depending on the influence that it receives in the period of fetal formation.
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27
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Abstract
Hypopituitarism is defined as a decreased release of hypophyseal hormones, which may be caused by disease of the pituitary gland disease or hypothalamus. The clinical findings of neonatal hypopituitarism depend on the causes and on presence and extent of hormonal deficiency. Patients may be asymptomatic or may demonstrate non-specific symptoms, but may still be at risk for development of pituitary hormone deficiency over time. Patient history, physical examination, endocrinological, radiological and genetic evaluations are all important for early diagnosis and treatment. The aim of this paper was to present a review of etiological factors, clinical findings, diagnosis and treatment approaches in neonatal hypopituitarism.
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Affiliation(s)
- Selim Kurtoğlu
- Erciyes University Faculty of Medicine, Department of Pediatrics, Division of Neonatalogy, Kayseri, Turkey,Erciyes University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Kayseri, Turkey
| | - Ahmet Özdemir
- Erciyes University Faculty of Medicine, Department of Pediatrics, Division of Neonatalogy, Kayseri, Turkey,* Address for Correspondence: Erciyes University Faculty of Medicine, Department of Pediatrics, Division of Neonatalogy, Kayseri, Turkey Phone: +90 352 207 66 66 E-mail:
| | - Nihal Hatipoğlu
- Erciyes University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Kayseri, Turkey
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28
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Zhao H, Zhang S, Wu X, Pan C, Li X, Lei C, Chen H, Lan X. DNA methylation pattern of the goat PITX1 gene and its effects on milk performance. Arch Anim Breed 2019; 62:59-68. [PMID: 31807614 PMCID: PMC6852879 DOI: 10.5194/aab-62-59-2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 01/24/2019] [Indexed: 12/23/2022] Open
Abstract
Paired-like homeodomain transcription factor 1 (PITX1) is a pivotal
gene in the hypothalamic–pituitary–adrenal axis, which is a well-known
pathway affecting lactation performance. The aim of this study was to analyze
the DNA methylation profile of the PITX1 gene and its relevance to
milk performance in Xinong Saanen dairy goats; thus, potential epigenetic
markers of lactation performance were identified. A total of 267 goat blood
samples were divided into “low” and “high” groups according to two milk
traits: the average milk yield (AMY) and the average milk density (AMD). One
CpG island in the 3′-flanking region of the PITX1 gene was
identified as being related to milk performance. Fisher's exact test
demonstrated that the methylation rates of the overall CpG island and the 3rd
and 12th CpG-dinucleotide loci in the blood were significantly associated
with the AMY, and the overall methylation rate of the high AMY group was
relative hypomethylation compared with the low AMY group. The overall
methylation rates of this CpG island in mammary gland tissue from dry and
lactation periods again exhibited a significant difference: the lactation
period showed relative hypomethylation compared with the dry period.
Bioinformatic transcription factor binding site prediction identified some
lactation performance related transcription factors in this CpG island, such
as CTCF, STAT, SMAD, CDEF, SP1, and KLFS. Briefly, overall methylation
changes of the CpG island in the PITX1 gene are relevant to
lactation performance, which will be valuable for future studies and
epigenetic marker-assisted selection (eMAS) in the breeding of goats with
respect to lactation performance.
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Affiliation(s)
- Haiyu Zhao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Sihuan Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Xianfeng Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Chuanying Pan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Xiangchen Li
- Institute of Beijing Animal Science and Veterinary, Chinese Academy of Agricultural Science, Beijing 100194, China
| | - Chuzhao Lei
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Hong Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Xianyong Lan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
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29
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Scala M, Accogli A, Allegri AME, Tassano E, Severino M, Morana G, Maghnie M, Capra V. Familial ROBO1 deletion associated with ectopic posterior pituitary, duplication of the pituitary stalk and anterior pituitary hypoplasia. J Pediatr Endocrinol Metab 2019; 32:95-99. [PMID: 30530901 DOI: 10.1515/jpem-2018-0272] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 11/17/2018] [Indexed: 12/12/2022]
Abstract
Background The genetic causes of abnormal pituitary development have been extensively studied in the last few years. ROBO1 is involved in neurogenesis and axon guidance. Loss-of-function variants in ROBO1 have been associated with pituitary stalk interruption syndrome (PSIS), suggesting that its haploinsufficiency could impair the guidance of hypothalamic axons to the pituitary gland leading to developmental abnormalities. Case presentation We report a 4.5-year-old girl with anterior pituitary hypoplasia and pituitary stalk duplication in the ventral-dorsal direction. Her father had a similar pituitary phenotype, characterized by anterior pituitary hypoplasia combined with ectopic posterior pituitary. Comparative genomic hybridization (CGH) microarray analysis identified a 343.7 kb deletion of 3p12.3 encompassing ROBO1 in both individuals. Conclusions We report the first familial ROBO1 deletion in two individuals with peculiar pituitary anomalies, including the rare pituitary stalk duplication in the ventral-dorsal direction. These findings widen the spectrum of the phenotypes associated with ROBO1 haploinsufficiency and support its role in human pituitary development.
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Affiliation(s)
- Marcello Scala
- UOC Neurochirurgia, Istituto Giannina Gaslini, Genoa, Italy
- Università degli Studi di Genova, Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Genoa, Italy
| | - Andrea Accogli
- UOC Neurochirurgia, Istituto Giannina Gaslini, Genoa, Italy
- Università degli Studi di Genova, Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Genoa, Italy
| | | | - Elisa Tassano
- Laboratorio di Citogenetica, Istituto Giannina Gaslini, Genoa, Italy
| | | | - Giovanni Morana
- UOC Neuroradiologia, Istituto Giannina Gaslini, Genoa, Italy
| | - Mohamad Maghnie
- Università degli Studi di Genova, Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Genoa, Italy
- UOC Clinica Pediatrica, Istituto Giannina Gaslini, Genoa, Italy
| | - Valeria Capra
- UOC Neurochirurgia, Istituto Giannina Gaslini, Genoa, Italy
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30
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Ishida K, Saito T, Mitsui T. Involvement of selective epithelial cell death in the formation of feather buds on a bioengineered skin. Dev Growth Differ 2019; 61:141-149. [PMID: 30675906 DOI: 10.1111/dgd.12593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 11/15/2018] [Accepted: 12/04/2018] [Indexed: 11/28/2022]
Abstract
Selective cell death by apoptosis plays important roles in organogenesis. Apoptotic cells are observed in the developmental and homeostatic processes of several ectodermal organs, such as hairs, feathers, and mammary glands. In chick feather development, apoptotic events have been observed during feather morphogenesis, but have not been investigated during early feather bud formation. Previously, we have reported a method for generating feather buds on a bioengineered skin from dissociated skin epithelial and mesenchymal cells in three-dimensional culture. During the development of the bioengineered skin, epithelial cavity formation by apoptosis was observed in the epithelial tissue. In this study, we examined the selective epithelial cell death during the bioengineered skin development. Histological analyses suggest that the selective epithelial cell death in the bioengineered skin was induced by caspase-3-related apoptosis. The formation of feather buds of the bioengineered skin was disturbed by the treatment with a pan-caspase inhibitor. The pan-caspase inhibitor treatment suppressed the rearrangement of the epithelial layer and the formation of dermal condensation, which are thought to be essential step to form feather buds. The suppression of the formation of feather buds on the pan-caspase inhibitor-treated skin was partially compensated by the addition of a GSK-3β inhibitor, which activates Wnt/β-catenin signaling. These results suggest that the epithelial cell death is involved in the formation of feather buds of the bioengineered skin. These observations also suggest that caspase activities and Wnt/β-catenin signaling may contribute to the formation of epithelial and mesenchymal components in the bioengineered skin.
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Affiliation(s)
- Kentaro Ishida
- Department of Physics and Mathematics, College of Science and Engineering, Aoyama Gakuin University, Kanagawa, Japan.,Department of Developmental Biology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuichiro Saito
- Department of Developmental Biology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Toshiyuki Mitsui
- Department of Physics and Mathematics, College of Science and Engineering, Aoyama Gakuin University, Kanagawa, Japan
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31
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Zhang S, Zhao H, Lei C, Pan C, Chen H, Lin Q, Lan X. Effects of genetic variations within goat PITX2 gene on growth traits and mRNA expression. Anim Biotechnol 2019; 31:107-114. [PMID: 30652937 DOI: 10.1080/10495398.2018.1551229] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Paired-like homeodomain 2 (PITX2), a key gene in hypothalamic-pituitary-adrena axis, influences animal growth and development. The objective of this study was to identify the association of the functional genetic variations within goat PITX2 gene with growth traits and mRNA expression levels. According to the reported single nucleotide polymorphisms (SNPs) information in Guanzhong dairy goat (GZDG), we identified genotypes of the known SNPs in Hainan black goat (HNBG). Association analysis uncovered that the SNPs of AC_000163: g.18117T > C, g.18161C > G and g.18353T > C loci were significantly associated with several growth traits (e.g., body height and body length) in HNBG and GZDG breeds. According to the quantitative real-time PCR assay, β-Actin and ribosomal protein L19 (RPL19) were the most stable expressed housekeeping genes in heart and skeletal muscle, respectively; meanwhile, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was the most stable expressed housekeeping gene in the other tissues. Based on the best housekeeping gene of varied tissues, we found the different genotypes of above loci were significantly associated with PITX2 mRNA expression in heart, muscle and small intestine. Briefly, the genetic variants of goat PITX2 associating with mRNA expression affected growth traits significantly, which would benefit for goat breeding in the future.
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Affiliation(s)
- Sihuan Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, P. R. China
| | - Haiyu Zhao
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, P. R. China
| | - Chuzhao Lei
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, P. R. China
| | - Chuanying Pan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, P. R. China
| | - Hong Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, P. R. China
| | - Qing Lin
- College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, P. R. China.,State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, Qinghai 810016, P. R. China
| | - Xianyong Lan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, P. R. China
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Yao X, Zhang Y, Wu L, Cheng R, Li C, Qu C, Ji H. Immunohistochemical Study of NR2C2, BTG2, TBX19, and CDK2 Expression in 31 Paired Primary/Recurrent Nonfunctioning Pituitary Adenomas. Int J Endocrinol 2019; 2019:5731639. [PMID: 31223310 PMCID: PMC6541973 DOI: 10.1155/2019/5731639] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 03/12/2019] [Accepted: 04/03/2019] [Indexed: 12/17/2022] Open
Abstract
This study investigated potential markers for predicting nonfunctioning pituitary adenoma (NFPA) invasion and recurrence by high-throughput tissue microarray analyses. We retrospectively studied two groups of patients: 60 nonrecurrent NFPA cases that included noninvasion and invasion subtypes and 43 recurrent cases that included primary NFPA. A total of 31 paired patient samples were evaluated (12 patients with one surgery and 31 who had undergone two operations, with both tumors analyzed). Expressions of nuclear receptor subfamily 2 group C member 2 (NR2C2), B cell translocation gene 2, T-box-19 (TBX19), and cyclin-dependent kinase 2 (CDK2) in surgically resected specimens were assessed by immunohistochemistry. The relationships between marker expression and clinical characteristics including age, sex, tumor volume, and follow-up time were analyzed. Tumor volume and invasion as well as follow-up time were significantly associated with invasion and recurrence (P < 0.01). Of the 60 nonrecurrent samples, 15/41 and 13/19 showed high NR2C2 expression in the noninvasion and invasion groups, respectively (χ 2 =5.287, P = 0.021). NR2C2 was also overexpressed in 43 primary recurrent cases (χ 2 =5.433, P = 0.02), whereas CDK2 (χ 2 = 11.242, P = 0.001) and TBX19 (χ 2 = 4.875, P = 0.027) were downregulated. In the 31 paired samples, NR2C2 was more highly expressed in the recurrent as compared to the primary tumor. High NR2C2 expression was associated with NFPA invasion, recurrence, and progression, while TBX19 and CDK2 were associated with NFPA recurrence.
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Affiliation(s)
- Xiaohui Yao
- Shanxi Provincial People's Hospital, Taiyuan, Shanxi Province, China
| | - Yazhuo Zhang
- Key Laboratory of Central Nervous System Injury Research, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Lijuan Wu
- Shanxi Provincial People's Hospital, Taiyuan, Shanxi Province, China
| | - Rui Cheng
- Shanxi Provincial People's Hospital, Taiyuan, Shanxi Province, China
| | - Chuzhong Li
- Key Laboratory of Central Nervous System Injury Research, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Chongxiao Qu
- Shanxi Provincial People's Hospital, Taiyuan, Shanxi Province, China
| | - Hongming Ji
- Shanxi Provincial People's Hospital, Taiyuan, Shanxi Province, China
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Gregory LC, Dattani MT. Embryologic and Genetic Disorders of the Pituitary Gland. CONTEMPORARY ENDOCRINOLOGY 2019:3-27. [DOI: 10.1007/978-3-030-11339-1_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Peel MT, Ho Y, Liebhaber SA. Transcriptome Analyses of Female Somatotropes and Lactotropes Reveal Novel Regulators of Cell Identity in the Pituitary. Endocrinology 2018; 159:3965-3980. [PMID: 30247555 PMCID: PMC6260062 DOI: 10.1210/en.2018-00587] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 09/18/2018] [Indexed: 12/31/2022]
Abstract
The differentiation of the hormone-producing cell lineages of the anterior pituitary represents an informative model of mammalian cell fate determination. The generation and maintenance of two of these lineages, the GH-producing somatotropes and prolactin (PRL)-producing lactotropes, are dependent on the pituitary-specific transcription factor POU1F1. Whereas POU1F1 is expressed in both cell types, and plays a direct role in the activation of both the Gh and Prl genes, GH expression is restricted to somatotropes and PRL expression is restricted to lactotropes. These observations imply the existence of additional, cell type-enriched factors that contribute to the somatotrope and lactotrope cell identities. In this study, we use transgenic mouse models to facilitate sorting of somatotrope and lactotrope populations based on the expression of fluorescent markers expressed under Gh and Prl gene transcriptional controls. The transcriptomic analyses reveal a concordance of gene expression profiles in the two populations. The limited number of divergent mRNAs between the two populations includes a set of transcription factors that may have roles in pituitary lineage divergence and/or in regulating expression of cell type-specific genes after differentiation. Four of these factors were validated for lineage enrichment at the level of protein expression, two somatotrope enriched and two lactotrope enriched. Three of these four factors were shown to have corresponding activities in appropriate enhancement or repression of landmark genes in a cell culture model system. These studies identify novel regulators of the somatotropes and lactotropes, and they establish a useful database for further study of these lineages in the anterior pituitary.
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Affiliation(s)
- Michael T Peel
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Yugong Ho
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Stephen A Liebhaber
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Correspondence: Stephen A. Liebhaber, MD, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Clinical Research Building, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104. E-mail:
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Gene polymorphisms in PROP1 associated with growth traits in sheep. Gene 2018; 683:41-46. [PMID: 30316920 DOI: 10.1016/j.gene.2018.10.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 09/03/2018] [Accepted: 10/09/2018] [Indexed: 01/13/2023]
Abstract
The PROP paired-like homeobox 1 (PROP1) gene encodes a protein that regulates growth and development in mammals. Possessing DNA-binding and transcriptional activation abilities, PROP1 is able to control the expression of crucial anterior pituitary hormones including growth hormone, thyroid-stimulating hormone, and prolactin. The objective of this study was to identify genetic variation in ovine PROP1 in 670 New Zealand Romney sheep. Three single nucleotide polymorphisms (SNPs) were detected, two of which located in intron 1 were novel (c.109+40 T>C and c.109+207C>T), whilst the one located in exon 1 (c.45A>G) had been previously reported. These SNPs were arranged into three haplotypic variants - A1, B1 and C1. At each locus, all three genotypes were observed with frequencies in accordance with the Hardy-Weinberg Equilibrium. Association analysis revealed that the variant GG, CC and CC genotypes for c.45A>G, c.109+40 T>C and c.109+207C>T respectively were significantly associated with higher lamb tailing and weaning weights, and growth rate-to-weaning. The A1 haplotype had a positive effect on tailing weight, weaning weight and growth rate, while the B1 haplotype impacted growth traits negatively. These findings suggest that variations in ovine PROP1 could serve as potential genetic markers for use in marker-assisted selection and the breeding for animals with superior growth traits.
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Genome-wide analyses of the Jeju, Thoroughbred, and Jeju crossbred horse populations using the high density SNP array. Genes Genomics 2018; 40:1249-1258. [PMID: 30099720 DOI: 10.1007/s13258-018-0722-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Accepted: 07/24/2018] [Indexed: 12/23/2022]
Abstract
The Jeju horse is an indigenous Korean horse breed that is currently registered with the Food and Agriculture Organization of the United Nations. However, there is severe lack of genomic studies on Jeju horse. This study was conducted to investigate genetic characteristics of horses including Jeju horse, Thoroughbred and Jeju crossbred (Jeju × Thoroughbred) populations. We compared the genomes of three horse populations using the Equine SNP70 Beadchip array. Short-range Linkage disequilibrium was the highest in Thoroughbred, whereas r2 values were lowest in Jeju horse. Expected heterozygosity was the highest in Jeju crossbred (0.351), followed by the Thoroughbred (0.337) and Jeju horse (0.311). The level of inbreeding was slightly higher in Thoroughbred (- 0.009) than in Jeju crossbred (- 0.035) and Jeju horse (- 0.038). FST value was the highest between Jeju horse and Thoroughbred (0.113), whereas Jeju crossbred and Thoroughbred showed the lowest value (0.031). The genetic relationship was further assessed by principal component analysis, suggesting that Jeju crossbred is more genetically similar to Thoroughbred than Jeju horse population. Additionally, we detected potential selection signatures, for example, in loci located on LCORL/NCAPG and PROP1 genes that are known to influence body. Genome-wide analyses of the three horse populations showed that all the breeds had somewhat a low level of inbreeding within each population. In the population structure analysis, we found that Jeju crossbred was genetically closer to Thoroughbred than Jeju horse. Furthermore, we identified several signatures of selection which might be associated with traits of interest. To our current knowledge, this study is the first genomic research, analyzing genetic relationships of Jeju horse, Thoroughbred and Jeju crossbred.
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Zhang S, Xu H, Kang Z, Cai H, Dang R, Lei C, Chen H, Guo X, Lan X. Bovine pituitary homeobox 2 (PITX2): mRNA expression profiles of different alternatively spliced variants and association analyses with growth traits. Gene 2018; 669:1-7. [DOI: 10.1016/j.gene.2018.05.083] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 05/12/2018] [Accepted: 05/21/2018] [Indexed: 12/19/2022]
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Fletcher PA, Sherman A, Stojilkovic SS. Common and diverse elements of ion channels and receptors underlying electrical activity in endocrine pituitary cells. Mol Cell Endocrinol 2018; 463:23-36. [PMID: 28652171 PMCID: PMC5742314 DOI: 10.1016/j.mce.2017.06.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 06/20/2017] [Accepted: 06/22/2017] [Indexed: 12/30/2022]
Abstract
The pituitary gland contains six types of endocrine cells defined by hormones they secrete: corticotrophs, melanotrophs, gonadotrophs, thyrotrophs, somatotrophs, and lactotrophs. All these cell types are electrically excitable, and voltage-gated calcium influx is the major trigger for their hormone secretion. Along with hormone intracellular content, G-protein-coupled receptor and ion channel expression can also be considered as defining cell type identity. While many aspects of the developmental and activity dependent regulation of hormone and G-protein-coupled receptor expression have been elucidated, much less is known about the regulation of the ion channels needed for excitation-secretion coupling in these cells. We compare the spontaneous and receptor-controlled patterns of electrical signaling among endocrine pituitary cell types, including insights gained from mathematical modeling. We argue that a common set of ionic currents unites these cells, while differential expression of another subset of ionic currents could underlie cell type-specific patterns. We demonstrate these ideas using a generic mathematical model, showing that it reproduces many observed features of pituitary electrical signaling. Mapping these observations to the developmental lineage suggests possible modes of regulation that may give rise to mature pituitary cell types.
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Affiliation(s)
- Patrick A Fletcher
- Laboratory of Biological Modeling, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
| | - Arthur Sherman
- Laboratory of Biological Modeling, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD, USA
| | - Stanko S Stojilkovic
- Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA
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Zhao H, He S, Wang S, Zhu Y, Xu H, Luo R, Lan X, Cai Y, Sun X. Two New Insertion/Deletion Variants of the PITX2 Gene and their Effects on Growth Traits in Sheep. Anim Biotechnol 2017; 29:276-282. [PMID: 29200321 DOI: 10.1080/10495398.2017.1379415] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
In China, Tong sheep (TS) and Lanzhou fat-tailed sheep (LFTS) are two closely relative endanger breeds for low meat production and low fecundity, finding some marker-assisted selected (MAS) is our first priority for improving their growth traits. For this purpose, Hu sheep (HS) and small-tailed Han sheep (STHS) were compared with two endangered breeds (TS and LFTS). Paired-liked homeodomain transcription factor 2 (PITX2) gene was the important member of PITX family, which could adjust animal growth through hypothalamic-pituitary-adrenal axis. During the past years, insertion/deletion (indel) has become increasingly popular in application as MAS. In this study, two novel indel loci were identified, and five significant differences, including chest width, hip width, chest depth, chest circumference, and body height, were found between different breeds. Interestingly, there was no DD genotype and smaller number of ID genotye. All the ID genotypes were significantly greater than II genotype, which was to say the allele of "D" was dominant variation and its frequency was lower, which demonstrated that it has huge space for selection. Briefly, the two indel were potential and useful DNA markers for selecting excellent individuals in relation to growth traits in sheep.
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Affiliation(s)
- Haidong Zhao
- a College of Animal Science and Technology , Northwest A&F University , Yangling , China
| | - Shuai He
- a College of Animal Science and Technology , Northwest A&F University , Yangling , China
| | - Shuhui Wang
- a College of Animal Science and Technology , Northwest A&F University , Yangling , China
| | - Yanjiao Zhu
- a College of Animal Science and Technology , Northwest A&F University , Yangling , China
| | - Hongwei Xu
- b Science Experimental Center , Northwest University for Nationalities , Lanzhou , China
| | - Renyun Luo
- c Ruilin Sci-Tech Culture and Breeding Limit Company , Yongjing , China
| | - Xianyong Lan
- a College of Animal Science and Technology , Northwest A&F University , Yangling , China
| | - Yong Cai
- c Ruilin Sci-Tech Culture and Breeding Limit Company , Yongjing , China.,d College of Life Science and Engineering , Northwest University for Nationalities , Lanzhou , China
| | - Xiuzhu Sun
- a College of Animal Science and Technology , Northwest A&F University , Yangling , China
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40
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Madeira JL, Nishi MY, Nakaguma M, Benedetti AF, Biscotto IP, Fernandes T, Pequeno T, Figueiredo T, Franca MM, Correa FA, Otto AP, Abrão M, Miras MB, Santos S, Jorge AA, Costalonga EF, Mendonca BB, Arnhold IJ, Carvalho LR. Molecular analysis of brazilian patients with combined pituitary hormone deficiency and orthotopic posterior pituitary lobe reveals eight different PROP1 alterations with three novel mutations. Clin Endocrinol (Oxf) 2017; 87:725-732. [PMID: 28734020 DOI: 10.1111/cen.13430] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Revised: 06/22/2017] [Accepted: 07/17/2017] [Indexed: 01/25/2023]
Abstract
BACKGROUND Mutations in PROP1, HESX1 and LHX3 are associated with combined pituitary hormone deficiency (CPHD) and orthotopic posterior pituitary lobe (OPP). OBJECTIVE To identify mutations in PROP1, HESX1 and LHX3 in a large cohort of patients with CPHD and OPP (35 Brazilian, two Argentinian). DESIGN AND METHODS We studied 23 index patients with CPHD and OPP (six familial and 17 sporadic) as well as 14 relatives. PROP1 was sequenced by the Sanger method in all except one sporadic case studied using a candidate gene panel. Multiplex ligation-dependent probe amplification (MLPA) was applied to one familial case in whom PROP1 failed to amplify by PCR. In the 13 patients without PROP1 mutations, HESX1 and LHX3 were sequenced by the Sanger method. RESULTS We identified PROP1 mutations in 10 index cases. Three mutations were novel: one affecting the initiation codon (c.1A>G) and two affecting splicing sites, c.109+1G>A and c.342+1G>C. The known mutations, c.150delA (p.Arg53Aspfs*112), c.218G>A (p.Arg73His), c.263T>C (p.Phe88Ser) and c.301_302delAG (p.Leu102Cysfs*8), were also detected. MLPA confirmed complete PROP1 deletion in one family. We did not identify HESX1 and LHX3 mutations by Sanger. CONCLUSION PROP1 mutations are a prevalent cause of congenital CPHD with OPP, and therefore, PROP1 sequencing must be the first step of molecular investigation in patients with CPHD and OPP, especially in populations with a high frequency of PROP1 mutations. In the absence of mutations, massively parallel sequencing is a promising approach. The high prevalence and diversity of PROP1 mutations is associated with the ethnic background of this cohort.
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Affiliation(s)
- Joao Lo Madeira
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Mirian Y Nishi
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Marilena Nakaguma
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Anna F Benedetti
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Isabela Peixoto Biscotto
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Thamiris Fernandes
- Departamento de Clínica Médica da Faculdade de Medicina da Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Thiago Pequeno
- Núcleo de Estudos em Genética e Educação, Universidade Estadual da Paraíba, Campina Grande, Paraíba, Brazil
| | - Thalita Figueiredo
- Núcleo de Estudos em Genética e Educação, Universidade Estadual da Paraíba, Campina Grande, Paraíba, Brazil
| | - Marcela M Franca
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Fernanda A Correa
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Aline P Otto
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Milena Abrão
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Mirta B Miras
- Servicio de Endocrinología Hospital de Niños de la Santísima Trinidad Córdoba, Córdoba, Argentina
| | - Silvana Santos
- Núcleo de Estudos em Genética e Educação, Universidade Estadual da Paraíba, Campina Grande, Paraíba, Brazil
| | - Alexander Al Jorge
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
- Unidade de Endocrinologia-Genética - LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Everlayny F Costalonga
- Departamento de Clínica Médica da Faculdade de Medicina da Universidade Federal do Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Berenice B Mendonca
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Ivo Jp Arnhold
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
| | - Luciani R Carvalho
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
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Xu H, Zhang S, Zhang X, Dang R, Lei C, Chen H, Lan X. Evaluation of novel SNPs and haplotypes within the <i>ATBF1</i> gene and their effects on economically important production traits in cattle. Arch Anim Breed 2017. [DOI: 10.5194/aab-60-285-2017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
Abstract. AT motif binding factor 1 (ATBF1) gene can promote the expression level of the growth hormone 1 (GH1) gene by binding to the enhancers of the POU1F1 and PROP1 genes; thus, it affects the growth and development of livestock. Considering that the ATBF1 gene also has a close relationship with the Janus kinase–signal transductor and activator of transcription (JAK–STAT) pathway, the objective of this work was to identify novel single-nucleotide polymorphism (SNP) variations and their association with growth traits in native Chinese cattle breeds. Five novel SNPs within the ATBF1 gene were found in 644 Qinchuan and Jinnan cattle for first time using 25 pairs of screening and genotyping primers. The five novel SNPs were named as AC_000175:g.140344C>G (SNP1), g.146573T>C (SNP2), g.205468C>T (SNP3), g.205575A>G (SNP4) and g.297690C<T (SNP5). Among them, SNP1 and SNP2 were synonymous coding SNPs, while SNP5 was a missense coding SNP, and the other SNPs were intronic. Haplotype analysis found 18 haplotypes in the two breeds, and three and five closely linked loci were revealed in Qinchuan and Jinnan breeds, respectively. Association analysis revealed that SNP1 was significantly associated with the height across the hip in Qinchuan cattle. SNP2 was found to be significantly related to chest circumference and body side length traits in Jinnan cattle. SNP3 was found to have significant associations with four growth traits in Qinchuan cattle. Moreover, the different combined genotypes, SNP1–SNP3, SNP1–SNP4 and SNP2–SNP5 were significantly associated with the growth traits in cattle. These findings indicated that the bovine ATBF1 gene had marked effects on growth traits, and the growth-trait-related loci can be used as DNA markers for maker-assisted selection (MAS) breeding programs in cattle.
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Bashamboo A, Bignon-Topalovic J, Moussi N, McElreavey K, Brauner R. Mutations in the Human ROBO1 Gene in Pituitary Stalk Interruption Syndrome. J Clin Endocrinol Metab 2017; 102:2401-2406. [PMID: 28402530 DOI: 10.1210/jc.2016-1095] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 04/06/2017] [Indexed: 12/21/2022]
Abstract
Context Pituitary stalk interruption syndrome (PSIS) is characterized by a thin or absent pituitary stalk usually in association with an ectopic posterior pituitary and hypoplasia/aplasia of the anterior pituitary. Associated phenotypes include varied ocular anomalies, hypoglycemia, micropenis/cryptorchidism, growth failure, or combined pituitary hormone deficiencies. Although genetic causes have been identified, they explain only around 5% of PSIS cases. Objective To identify genetic causes of PSIS by exome sequencing. Design Exon enrichment was performed using the Agilent SureSelect Human All Exon V4. Paired-end sequencing was performed on the Illumina HiSeq2000 platform with an average sequencing coverage of ×50. Patients Patients with unexplained PSIS were included in the study. Results In five cases of unexplained PSIS including two familial cases, we identified a novel heterozygous frameshift and nonsense and missense mutations in the ROBO1 gene (p.Ala977Glnfs*40, two affected sibs; p.Tyr1114Ter, sporadic case, and p.Cys240Ser, affected child and paternal aunt) that controls embryonic axon guidance, and branching in the nervous system. Interestingly, four of the five cases of PSIS also presented with ocular anomalies, including hypermetropia with strabismus as well as ptosis. Conclusions These data suggest that mutations in ROBO1 contribute to PSIS and associated ocular anomalies.
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Affiliation(s)
- Anu Bashamboo
- Human Developmental Genetics, Institut Pasteur, 75015 Paris, France
| | | | - Nasser Moussi
- Human Developmental Genetics, Institut Pasteur, 75015 Paris, France
| | - Ken McElreavey
- Human Developmental Genetics, Institut Pasteur, 75015 Paris, France
| | - Raja Brauner
- Université Paris Descartes and Pediatric Endocrinology Unit, Fondation Ophtalmologique Adolphe de Rothschild, 75019 Paris, France
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Yoshida S, Kato T, Kanno N, Nishimura N, Nishihara H, Horiguchi K, Kato Y. Cell type-specific localization of Ephs pairing with ephrin-B2 in the rat postnatal pituitary gland. Cell Tissue Res 2017; 370:99-112. [PMID: 28660300 DOI: 10.1007/s00441-017-2646-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 05/06/2017] [Indexed: 01/20/2023]
Abstract
Sox2-expressing stem/progenitor cells in the anterior lobe of the pituitary gland form two types of micro-environments (niches): the marginal cell layer and dense cell clusters in the parenchyma. In relation to the mechanism of regulation of niches, juxtacrine signaling via ephrin and its receptor Eph is known to play important roles in various niches. The ephrin and Eph families are divided into two subclasses to create ephrin/Eph signaling in co-operation with confined partners. Recently, we reported that ephrin-B2 localizes specifically to both pituitary niches. However, the Ephs interacting with ephrin-B2 in these pituitary niches have not yet been identified. Therefore, the present study aims to identify the Ephs interacting with ephrin-B2 and the cells that produce them in the rat pituitary gland. In situ hybridization and immunohistochemistry demonstrated cell type-specific localization of candidate interacting partners for ephrin-B2, including EphA4 in cells located in the posterior lobe, EphB1 in gonadotropes, EphB2 in corticotropes, EphB3 in stem/progenitor cells and EphB4 in endothelial cells in the adult pituitary gland. In particular, double-immunohistochemistry showed cis-interactions between EphB3 and ephrin-B2 in the apical cell membranes of stem/progenitor cell niches throughout life and trans-interactions between EphB2 produced by corticotropes and ephrin-B2 located in the basolateral cell membranes of stem/progenitor cells in the early postnatal pituitary gland. These data indicate that ephrin-B2 plays a role in pituitary stem/progenitor cell niches by selective interaction with EphB3 in cis and EphB2 in trans.
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Affiliation(s)
- Saishu Yoshida
- Division of Life Science, Graduate School of Agriculture, Meiji University, Kanagawa, Japan.,Institute of Reproduction and Endocrinology, Meiji University, Kanagawa, Japan
| | - Takako Kato
- Institute of Reproduction and Endocrinology, Meiji University, Kanagawa, Japan
| | - Naoko Kanno
- Division of Life Science, Graduate School of Agriculture, Meiji University, Kanagawa, Japan
| | - Naoto Nishimura
- Division of Life Science, Graduate School of Agriculture, Meiji University, Kanagawa, Japan
| | - Hiroto Nishihara
- Division of Life Science, Graduate School of Agriculture, Meiji University, Kanagawa, Japan
| | - Kotaro Horiguchi
- Laboratory of Anatomy and Cell Biology, Department of Health Sciences, Kyorin University, Tokyo, Japan
| | - Yukio Kato
- Division of Life Science, Graduate School of Agriculture, Meiji University, Kanagawa, Japan. .,Institute of Reproduction and Endocrinology, Meiji University, Kanagawa, Japan. .,Department of Life Science, School of Agriculture, Meiji University, Kanagawa, Japan.
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Nistal M, Paniagua R, González-Peramato P, Reyes-Múgica M. Perspectives in Pediatric Pathology, Chapter 22. Testicular Involvement in Systemic Diseases. Pediatr Dev Pathol 2017; 19:431-451. [PMID: 25333836 DOI: 10.2350/14-09-1556-pb.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Normal testicular physiology requires appropriate function of endocrine glands and other tissues. Testicular lesions have been described in disorders involving the hypothalamus-hypophysis, thyroid glands, adrenal glands, pancreas, liver, kidney, and gastrointestinal tract. Testicular abnormalities can also associate with chronic anemia, obesity, and neoplasia. Although many of the disorders that affect the above-mentioned glands and tissues are congenital, acquired lesions may result in hypogonadism in children and adolescents.
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Affiliation(s)
- Manuel Nistal
- 1 Department of Pathology, Hospital La Paz, Universidad Autónoma de Madrid, Madrid 28029, Spain
| | - Ricardo Paniagua
- 2 Department of Cell Biology, Universidad de Alcala, Madrid, Spain
| | - Pilar González-Peramato
- 1 Department of Pathology, Hospital La Paz, Universidad Autónoma de Madrid, Madrid 28029, Spain
| | - Miguel Reyes-Múgica
- 3 Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA
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Clump formation in mouse pituitary-derived non-endocrine cell line Tpit/F1 promotes differentiation into growth-hormone-producing cells. Cell Tissue Res 2017; 369:353-368. [DOI: 10.1007/s00441-017-2603-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 02/24/2017] [Indexed: 01/08/2023]
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46
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Wang CZ, Guo LL, Han BY, Su X, Guo QH, Mu YM. Pituitary Stalk Interruption Syndrome: From Clinical Findings to Pathogenesis. J Neuroendocrinol 2017; 29. [PMID: 27917547 DOI: 10.1111/jne.12451] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 11/28/2016] [Accepted: 11/28/2016] [Indexed: 12/21/2022]
Abstract
Pituitary stalk interruption syndrome (PSIS) is a rare congenital defect manifesting with varying degrees of pituitary hormone deficiency. The signs and symptoms of PSIS during the neonatal period and infancy are often overlooked and therefore diagnosis is delayed. The typical manifestations of PSIS can be detected by magnetic resonance imaging. Several genes in the Wnt, Notch and Shh signalling pathways related to hypothalamic-pituitary development, such as PIT1, PROP1, LHX3/LHX4, PROKR2, OTX2, TGIF and HESX1, have been found to be associated with PSIS. Nevertheless, the aetiology in the majority of cases still remains unknown. In the present review, we provide an overview of clinical features of PSIS and summarise our current understanding of the underlying pathogenic mechanisms for this rare syndrome. Furthermore, we propose future research directions that may help our understanding of the aetiology of PSIS.
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Affiliation(s)
- C-Z Wang
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
| | - L-L Guo
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
- Department of Endocrinology, Beijing Electric Teaching Hospital of Capital Medical University, Beijing, 100073, China
| | - B-Y Han
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
| | - X Su
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
| | - Q-H Guo
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
- Department of Endocrinology, Hainan Branch of Chinese PLA General Hospital, Sanya, Hainan, 572000, China
| | - Y-M Mu
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853, China
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Pritchett EM, Lamont SJ, Schmidt CJ. Transcriptomic changes throughout post-hatch development in Gallus gallus pituitary. J Mol Endocrinol 2017; 58:43-55. [PMID: 27856505 PMCID: PMC5148799 DOI: 10.1530/jme-16-0186] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 11/17/2016] [Indexed: 12/04/2022]
Abstract
The pituitary gland is a neuroendocrine organ that works closely with the hypothalamus to affect multiple processes within the body including the stress response, metabolism, growth and immune function. Relative tissue expression (rEx) is a transcriptome analysis method that compares the genes expressed in a particular tissue to the genes expressed in all other tissues with available data. Using rEx, the aim of this study was to identify genes that are uniquely or more abundantly expressed in the pituitary when compared to all other collected chicken tissues. We applied rEx to define genes enriched in the chicken pituitaries at days 21, 22 and 42 post-hatch. rEx analysis identified 25 genes shared between all time points, 295 genes shared between days 21 and 22 and 407 genes unique to day 42. The 25 genes shared by all time points are involved in morphogenesis and general nervous tissue development. The 295 shared genes between days 21 and 22 are involved in neurogenesis and nervous system development and differentiation. The 407 unique day 42 genes are involved in pituitary development, endocrine system development and other hormonally related gene ontology terms. Overall, rEx analysis indicates a focus on nervous system/tissue development at days 21 and 22. By day 42, in addition to nervous tissue development, there is expression of genes involved in the endocrine system, possibly for maturation and preparation for reproduction. This study defines the transcriptome of the chicken pituitary gland and aids in understanding the expressed genes critical to its function and maturation.
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Affiliation(s)
| | | | - Carl J Schmidt
- Animal and Food ScienceUniversity of Delaware, Newark, Delaware, USA
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Fang Q, George AS, Brinkmeier ML, Mortensen AH, Gergics P, Cheung LYM, Daly AZ, Ajmal A, Pérez Millán MI, Ozel AB, Kitzman JO, Mills RE, Li JZ, Camper SA. Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era. Endocr Rev 2016; 37:636-675. [PMID: 27828722 PMCID: PMC5155665 DOI: 10.1210/er.2016-1101] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 10/31/2016] [Indexed: 02/08/2023]
Abstract
The genetic basis for combined pituitary hormone deficiency (CPHD) is complex, involving 30 genes in a variety of syndromic and nonsyndromic presentations. Molecular diagnosis of this disorder is valuable for predicting disease progression, avoiding unnecessary surgery, and family planning. We expect that the application of high throughput sequencing will uncover additional contributing genes and eventually become a valuable tool for molecular diagnosis. For example, in the last 3 years, six new genes have been implicated in CPHD using whole-exome sequencing. In this review, we present a historical perspective on gene discovery for CPHD and predict approaches that may facilitate future gene identification projects conducted by clinicians and basic scientists. Guidelines for systematic reporting of genetic variants and assigning causality are emerging. We apply these guidelines retrospectively to reports of the genetic basis of CPHD and summarize modes of inheritance and penetrance for each of the known genes. In recent years, there have been great improvements in databases of genetic information for diverse populations. Some issues remain that make molecular diagnosis challenging in some cases. These include the inherent genetic complexity of this disorder, technical challenges like uneven coverage, differing results from variant calling and interpretation pipelines, the number of tolerated genetic alterations, and imperfect methods for predicting pathogenicity. We discuss approaches for future research in the genetics of CPHD.
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Affiliation(s)
- Qing Fang
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Akima S George
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Michelle L Brinkmeier
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Amanda H Mortensen
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Peter Gergics
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Leonard Y M Cheung
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Alexandre Z Daly
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Adnan Ajmal
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - María Ines Pérez Millán
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - A Bilge Ozel
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Jacob O Kitzman
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Ryan E Mills
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Jun Z Li
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Sally A Camper
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
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Zhang X, Zhang S, Yang Q, Lei C, Chen H, Lan X. Exploration of dairy goat PITX2 alternative splice events and differential isoform expression. Small Rumin Res 2016. [DOI: 10.1016/j.smallrumres.2016.09.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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50
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S100β-Positive Cells of Mesenchymal Origin Reside in the Anterior Lobe of the Embryonic Pituitary Gland. PLoS One 2016; 11:e0163981. [PMID: 27695124 PMCID: PMC5047643 DOI: 10.1371/journal.pone.0163981] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 09/16/2016] [Indexed: 01/15/2023] Open
Abstract
The anterior and intermediate lobes of the pituitary gland develop through invagination of the oral ectoderm and as they are endocrine tissues, they participate in the maintenance of vital functions via the synthesis and secretion of numerous hormones. We recently observed that several extrapituitary cells invade the anterior lobe of the developing pituitary gland. This raised the question of the origin(s) of these S100β-positive cells, which are not classic endocrine cells but instead comprise a heterogeneous cell population with plural roles, especially as stem/progenitor cells. To better understand the roles of these S100β-positive cells, we performed immunohistochemical analysis using several markers in S100β/GFP-TG rats, which express GFP in S100β-expressing cells under control of the S100β promoter. GFP-positive cells were present as mesenchymal cells surrounding the developing pituitary gland and at Atwell's recess but were not present in the anterior lobe on embryonic day 15.5. These cells were negative for SOX2, a pituitary stem/progenitor marker, and PRRX1, a mesenchyme and pituitary stem/progenitor marker. However, three days later, GFP-positive and PRRX1-positive (but SOX2-negative) cells were observed in the parenchyma of the anterior lobe. Furthermore, some GFP-positive cells were positive for vimentin, p75, isolectin B4, DESMIN, and Ki67. These data suggest that S100β-positive cells of extrapituitary origin invade the anterior lobe, undergoing proliferation and diverse transformation during pituitary organogenesis.
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