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1
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Yu M, Vieta-Ferrer ER, Bakdalieh A, Tsai T. The Role of Visual Electrophysiology in Systemic Hereditary Syndromes. Int J Mol Sci 2025; 26:957. [PMID: 39940729 PMCID: PMC11816691 DOI: 10.3390/ijms26030957] [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] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
Visual electrophysiology is a valuable tool for evaluating the visual system in various systemic syndromes. This review highlights its clinical application in a selection of syndromes associated with hearing loss, mitochondrial dysfunction, obesity, and other multisystem disorders. Techniques such as full-field electroretinography (ffERG), multifocal electroretinography (mfERG), pattern electroretinography (PERG), visual evoked potentials (VEP), and electrooculography (EOG) offer insights into retinal and optic nerve function, often detecting abnormalities before clinical symptoms manifest. In hearing loss syndromes like Refsum disease, Usher syndrome (USH), and Wolfram syndrome (WS), electrophysiology facilitates the detection of early retinal changes that precede the onset of visual symptoms. For mitochondrial disorders such as maternally-inherited diabetes and deafness (MIDD), Kearns-Sayre syndrome (KSS), and neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, these tests can be useful in characterizing retinal degeneration and optic neuropathy. In obesity syndromes, including Bardet-Biedl syndrome (BBS), Alström syndrome, and Cohen syndrome, progressive retinal degeneration is a hallmark feature. Electrophysiological techniques aid in pinpointing retinal dysfunction and tracking disease progression. Other syndromes, such as Alagille syndrome (AGS), abetalipoproteinemia (ABL), Cockayne syndrome (CS), Joubert syndrome (JS), mucopolysaccharidosis (MPS), Neuronal ceroid lipofuscinoses (NCLs), and Senior-Løken syndrome (SLS), exhibit significant ocular involvement that can be evaluated using these methods. This review underscores the role of visual electrophysiology in diagnosing and monitoring visual system abnormalities across a range of syndromes, potentially offering valuable insights for early diagnosis, monitoring of progression, and management.
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Affiliation(s)
- Minzhong Yu
- Department of Ophthalmology and Visual Sciences, University Hospitals Eye Institute, Case Western Reserve University, Cleveland, OH 44106, USA
- Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA
- Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
| | | | - Anas Bakdalieh
- College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, USA;
| | - Travis Tsai
- School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
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2
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Zhang B, He P, Lawrence JEG, Wang S, Tuck E, Williams BA, Roberts K, Kleshchevnikov V, Mamanova L, Bolt L, Polanski K, Li T, Elmentaite R, Fasouli ES, Prete M, He X, Yayon N, Fu Y, Yang H, Liang C, Zhang H, Blain R, Chedotal A, FitzPatrick DR, Firth H, Dean A, Bayraktar OA, Marioni JC, Barker RA, Storer MA, Wold BJ, Zhang H, Teichmann SA. A human embryonic limb cell atlas resolved in space and time. Nature 2024; 635:668-678. [PMID: 38057666 PMCID: PMC7616500 DOI: 10.1038/s41586-023-06806-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 10/31/2023] [Indexed: 12/08/2023]
Abstract
Human limbs emerge during the fourth post-conception week as mesenchymal buds, which develop into fully formed limbs over the subsequent months1. This process is orchestrated by numerous temporally and spatially restricted gene expression programmes, making congenital alterations in phenotype common2. Decades of work with model organisms have defined the fundamental mechanisms underlying vertebrate limb development, but an in-depth characterization of this process in humans has yet to be performed. Here we detail human embryonic limb development across space and time using single-cell and spatial transcriptomics. We demonstrate extensive diversification of cells from a few multipotent progenitors to myriad differentiated cell states, including several novel cell populations. We uncover two waves of human muscle development, each characterized by different cell states regulated by separate gene expression programmes, and identify musculin (MSC) as a key transcriptional repressor maintaining muscle stem cell identity. Through assembly of multiple anatomically continuous spatial transcriptomic samples using VisiumStitcher, we map cells across a sagittal section of a whole fetal hindlimb. We reveal a clear anatomical segregation between genes linked to brachydactyly and polysyndactyly, and uncover transcriptionally and spatially distinct populations of the mesenchyme in the autopod. Finally, we perform single-cell RNA sequencing on mouse embryonic limbs to facilitate cross-species developmental comparison, finding substantial homology between the two species.
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Affiliation(s)
- Bao Zhang
- The Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Peng He
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - John E G Lawrence
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
- Department of Trauma and Orthopaedics, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, UK
| | - Shuaiyu Wang
- The Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Department of Obstetrics, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Elizabeth Tuck
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Brian A Williams
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Kenny Roberts
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | | | - Lira Mamanova
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
- Enhanc3D Genomics Ltd, Cambridge, UK
| | - Liam Bolt
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
- Genomics England, London, UK
| | | | - Tong Li
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Rasa Elmentaite
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Eirini S Fasouli
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
- Basic Research Center, Biomedical Research Foundation, Academy of Athens, Athens, Greece
| | - Martin Prete
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Xiaoling He
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Nadav Yayon
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Yixi Fu
- The Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Hao Yang
- The Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Chen Liang
- The Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Hui Zhang
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Raphael Blain
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
| | - Alain Chedotal
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France
- Institut de pathologie, groupe hospitalier Est, hospices civils de Lyon, Lyon, France
- University Claude Bernard Lyon 1, MeLiS, CNRS UMR5284, INSERM U1314, Lyon, France
| | | | - Helen Firth
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Andrew Dean
- Department of Clinical Neurosciences, Cambridge University Hospitals NHS Foundation, Cambridge, UK
| | | | - John C Marioni
- European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Roger A Barker
- John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Mekayla A Storer
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Barbara J Wold
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Hongbo Zhang
- The Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
- Advanced Medical Technology Center, the First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
| | - Sarah A Teichmann
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
- Theory of Condensed Matter Group, Department of Physics, Cavendish Laboratory, University of Cambridge, Cambridge, UK.
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3
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Taelman J, Czukiewska SM, Moustakas I, Chang YW, Hillenius S, van der Helm T, van der Meeren LE, Mei H, Fan X, Chuva de Sousa Lopes SM. Characterization of the human fetal gonad and reproductive tract by single-cell transcriptomics. Dev Cell 2024; 59:529-544.e5. [PMID: 38295793 PMCID: PMC10898717 DOI: 10.1016/j.devcel.2024.01.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 09/05/2023] [Accepted: 01/08/2024] [Indexed: 02/29/2024]
Abstract
During human fetal development, sex differentiation occurs not only in the gonads but also in the adjacent developing reproductive tract. However, while the cellular composition of male and female human fetal gonads is well described, that of the adjacent developing reproductive tract remains poorly characterized. Here, we performed single-cell transcriptomics on male and female human fetal gonads together with the adjacent developing reproductive tract from first and second trimesters, highlighting the morphological and molecular changes during sex differentiation. We validated different cell populations of the developing reproductive tract and gonads and compared the molecular signatures between the first and second trimesters, as well as between sexes, to identify conserved and sex-specific features. Together, our study provides insights into human fetal sex-specific gonadogenesis and development of the reproductive tract beyond the gonads.
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Affiliation(s)
- Jasin Taelman
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
| | - Sylwia M Czukiewska
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
| | - Ioannis Moustakas
- Sequencing Analysis Support Core, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
| | - Yolanda W Chang
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
| | - Sanne Hillenius
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
| | - Talia van der Helm
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
| | - Lotte E van der Meeren
- Department of Pathology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands; Department of Pathology, Erasmus Medical Center, 3015 GD Rotterdam, the Netherlands
| | - Hailiang Mei
- Sequencing Analysis Support Core, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
| | - Xueying Fan
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands.
| | - Susana M Chuva de Sousa Lopes
- Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands; Department for Reproductive Medicine, Ghent University Hospital, 9000 Ghent, Belgium.
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4
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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5
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Ayoub MD, Bakhsh AA, Vandriel SM, Keitel V, Kamath BM. Management of adults with Alagille syndrome. Hepatol Int 2023; 17:1098-1112. [PMID: 37584849 PMCID: PMC10522532 DOI: 10.1007/s12072-023-10578-x] [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] [Received: 05/09/2023] [Accepted: 07/30/2023] [Indexed: 08/17/2023]
Abstract
Alagille syndrome (ALGS) is a complex rare genetic disorder that involves multiple organ systems and is historically regarded as a disease of childhood. Since it is inherited in an autosomal dominant manner in 40% of patients, it carries many implications for genetic counselling of patients and screening of family members. In addition, the considerable variable expression and absence of a clear genotype-phenotype correlation, results in a diverse range of clinical manifestations, even in affected individuals within the same family. With recent therapeutic advancements in cholestasis treatment and the improved survival rates with liver transplantation (LT), many patients with ALGS survive into adulthood. Although LT is curative for liver disease secondary to ALGS, complications secondary to extrahepatic involvement remain problematic lifelong. This review is aimed at providing a comprehensive review of ALGS to adult clinicians who will take over the medical care of these patients following transition, with particular focus on certain aspects of the condition that require lifelong surveillance. We also provide a diagnostic framework for adult patients with suspected ALGS and highlight key aspects to consider when determining eligibility for LT in patients with this syndrome.
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Affiliation(s)
- Mohammed D Ayoub
- Department of Pediatrics, Faculty of Medicine, Rabigh Branch, King Abdulaziz University, Jeddah, Saudi Arabia
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON, M5G 1X8, Canada
| | - Ahmad A Bakhsh
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON, M5G 1X8, Canada
- Department of Pediatrics, Faculty of Medicine, University of Jeddah, Jeddah, Saudi Arabia
| | - Shannon M Vandriel
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON, M5G 1X8, Canada
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, Faculty of Medicine, Otto Von Guericke University Magdeburg, Magdeburg, Germany
| | - Binita M Kamath
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON, M5G 1X8, Canada.
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6
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Hankeova S, Van Hul N, Laznovsky J, Verboven E, Mangold K, Hensens N, Adori C, Verhoef E, Zikmund T, Dawit F, Kavkova M, Salplachta J, Sjöqvist M, Johansson BR, Hassan MG, Fredriksson L, Baumgärtel K, Bryja V, Lendahl U, Jheon A, Alten F, Fahnehjelm KT, Fischler B, Kaiser J, Andersson ER. Sex differences and risk factors for bleeding in Alagille syndrome. EMBO Mol Med 2022; 14:e15809. [PMID: 36345711 PMCID: PMC9728057 DOI: 10.15252/emmm.202215809] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 09/27/2022] [Accepted: 10/05/2022] [Indexed: 11/11/2022] Open
Abstract
Spontaneous bleeds are a leading cause of death in the pediatric JAG1-related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in bleeding events in patients, whether Jag1Ndr/Ndr mice display bleeds or vascular defects, and whether discovered vascular pathology can be confirmed in patients non-invasively. We performed a systematic review of patients with ALGS and vascular events following PRISMA guidelines, in the context of patient sex, and found significantly more girls than boys reported with spontaneous intracranial hemorrhage. We investigated vascular development, homeostasis, and bleeding in Jag1Ndr/Ndr mice, using retina as a model. Jag1Ndr/Ndr mice displayed sporadic brain bleeds, a thin skull, tortuous blood vessels, sparse arterial smooth muscle cell coverage in multiple organs, which could be aggravated by hypertension, and sex-specific venous defects. Importantly, we demonstrated that retinographs from patients display similar characteristics with significantly increased vascular tortuosity. In conclusion, there are clinically important sex differences in vascular disease in ALGS, and retinography allows non-invasive vascular analysis in patients. Finally, Jag1Ndr/Ndr mice represent a new model for vascular compromise in ALGS.
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Affiliation(s)
- Simona Hankeova
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
- Department of Experimental BiologyMasaryk UniversityBrnoCzech Republic
| | - Noemi Van Hul
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
| | - Jakub Laznovsky
- CEITEC – Central European Institute of TechnologyBrno University of TechnologyBrnoCzech Republic
| | - Elisabeth Verboven
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
| | - Katrin Mangold
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
| | - Naomi Hensens
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
- University of Applied Sciences UtrechtUtrechtThe Netherlands
| | - Csaba Adori
- Department of NeuroscienceKarolinska InstitutetStockholmSweden
| | - Elvira Verhoef
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
- University of Applied Sciences UtrechtUtrechtThe Netherlands
| | - Tomas Zikmund
- CEITEC – Central European Institute of TechnologyBrno University of TechnologyBrnoCzech Republic
| | - Feven Dawit
- Department of Pediatrics, Clinical Science, Intervention and Technology (CLINTEC)Karolinska Institutet and Karolinska University HospitalHuddingeSweden
| | - Michaela Kavkova
- CEITEC – Central European Institute of TechnologyBrno University of TechnologyBrnoCzech Republic
| | - Jakub Salplachta
- CEITEC – Central European Institute of TechnologyBrno University of TechnologyBrnoCzech Republic
| | - Marika Sjöqvist
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
| | - Bengt R Johansson
- EM Unit, Institute of BiomedicineUniversity of GothenburgGothenburgSweden
| | - Mohamed G Hassan
- University of San FranciscoSan FranciscoCAUSA
- Department of OrthodonticsFaculty of DentistryAssiut UniversityAssiutEgypt
| | - Linda Fredriksson
- Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
| | | | - Vitezslav Bryja
- Department of Experimental BiologyMasaryk UniversityBrnoCzech Republic
| | - Urban Lendahl
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
| | | | - Florian Alten
- Department of OphthalmologyUniversity of Muenster Medical CenterMünsterGermany
| | - Kristina Teär Fahnehjelm
- Department of Pediatric Ophthalmology, Strabismus, Electrophysiology and Ocular Oncology, St. Erik Eye HospitalKarolinska InstitutetStockholmSweden
- Department of Clinical NeuroscienceKarolinska InstitutetStockholmSweden
| | - Björn Fischler
- Department of Pediatrics, Clinical Science, Intervention and Technology (CLINTEC)Karolinska Institutet and Karolinska University HospitalHuddingeSweden
| | - Jozef Kaiser
- CEITEC – Central European Institute of TechnologyBrno University of TechnologyBrnoCzech Republic
| | - Emma R Andersson
- Department of Cell and Molecular BiologyKarolinska InstitutetStockholmSweden
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Ayoub MD, Kamath BM. Alagille Syndrome: Current Understanding of Pathogenesis, and Challenges in Diagnosis and Management. Clin Liver Dis 2022; 26:355-370. [PMID: 35868679 DOI: 10.1016/j.cld.2022.03.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Alagille syndrome (ALGS) is a complex heterogenous disease with a wide array of clinical manifestations in association with cholestatic liver disease. Major clinical and genetic advancements have taken place since its first description in 1969. However, clinicians continue to face considerable challenges in the management of ALGS, particularly in the absence of targeted molecular therapies. In this article, we provide an overview of the broad ALGS phenotype, current approaches to diagnosis and with particular focus on key clinical challenges encountered in the management of these patients.
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Affiliation(s)
- Mohammed D Ayoub
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada; Department of Pediatrics, Rabigh Branch, King Abdulaziz University, PO Box 80205, Jeddah 21589, Saudi Arabia
| | - Binita M Kamath
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
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Caiazza C, Parisi S, Caiazzo M. Liver Organoids: Updates on Disease Modeling and Biomedical Applications. BIOLOGY 2021; 10:835. [PMID: 34571712 PMCID: PMC8470787 DOI: 10.3390/biology10090835] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/20/2021] [Accepted: 08/24/2021] [Indexed: 12/12/2022]
Abstract
Liver organoids are stem cell-derived 3D structures that are generated by liver differentiation signals in the presence of a supporting extracellular matrix. Liver organoids overcome low complexity grade of bidimensional culture and high costs of in vivo models thus representing a turning point for studying liver disease modeling. Liver organoids can be established from different sources as induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), hepatoblasts and tissue-derived cells. This novel in vitro system represents an innovative tool to deeper understand the physiology and pathological mechanisms affecting the liver. In this review, we discuss the current advances in the field focusing on their application in modeling diseases, regenerative medicine and drug discovery.
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Affiliation(s)
- Carmen Caiazza
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy;
| | - Silvia Parisi
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy;
| | - Massimiliano Caiazzo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy;
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
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9
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Breikaa RM, Lilly B. The Notch Pathway: A Link Between COVID-19 Pathophysiology and Its Cardiovascular Complications. Front Cardiovasc Med 2021; 8:681948. [PMID: 34124207 PMCID: PMC8187573 DOI: 10.3389/fcvm.2021.681948] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/06/2021] [Indexed: 12/27/2022] Open
Abstract
COVID-19 is associated with a large number of cardiovascular sequelae, including dysrhythmias, myocardial injury, myocarditis and thrombosis. The Notch pathway is one likely culprit leading to these complications due to its direct role in viral entry, inflammation and coagulation processes, all shown to be key parts of COVID-19 pathogenesis. This review highlights links between the pathophysiology of SARS-CoV2 and the Notch signaling pathway that serve as primary drivers of the cardiovascular complications seen in COVID-19 patients.
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Affiliation(s)
- Randa M. Breikaa
- Center for Cardiovascular Research and The Heart Center, Nationwide Children's Hospital, Columbus, OH, United States
- Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH, United States
| | - Brenda Lilly
- Center for Cardiovascular Research and The Heart Center, Nationwide Children's Hospital, Columbus, OH, United States
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
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10
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Hess RA, Sharpe RM, Hinton BT. Estrogens and development of the rete testis, efferent ductules, epididymis and vas deferens. Differentiation 2021; 118:41-71. [PMID: 33441255 PMCID: PMC8026493 DOI: 10.1016/j.diff.2020.11.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 11/29/2020] [Indexed: 02/07/2023]
Abstract
Estrogen has always been considered the female hormone and testosterone the male hormone. However, estrogen's presence in the testis and deleterious effects of estrogen treatment during development have been known for nearly 90 years, long before estrogen receptors (ESRs) were discovered. Eventually it was learned that testes actually synthesize high levels of estradiol (E2) and sequester high concentrations in the reproductive tract lumen, which seems contradictory to the overwhelming number of studies showing reproductive pathology following exogenous estrogen exposures. For too long, the developmental pathology of estrogen has dominated our thinking, even resulting in the "estrogen hypothesis" as related to the testicular dysgenesis syndrome. However, these early studies and the development of an Esr1 knockout mouse led to a deluge of research into estrogen's potential role in and disruption of development and function of the male reproductive system. What is new is that estrogen action in the male cannot be divorced from that of androgen. This paper presents what is known about components of the estrogen pathway, including its synthesis and target receptors, and the need to achieve a balance between androgen- and estrogen-action in male reproductive tract differentiation and adult functions. The review focuses on what is known regarding development of the male reproductive tract, from the rete testis to the vas deferens, and examines the expression of estrogen receptors and presence of aromatase in the male reproductive system, traces the evidence provided by estrogen-associated knockout and transgenic animal models and discusses the effects of fetal and postnatal exposures to estrogens. Hopefully, there will be enough here to stimulate discussions and new investigations of the androgen:estrogen balance that seems to be essential for development of the male reproductive tract.
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Affiliation(s)
- Rex A Hess
- Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, IL, 61802 USA and Epivara, Inc., Research Park, 60 Hazelwood Dr., Suite 230G, Champaign, IL, 61820, USA.
| | - Richard M Sharpe
- MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
| | - Barry T Hinton
- Department of Cell Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.
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11
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Ayoub MD, Kamath BM. Alagille Syndrome: Diagnostic Challenges and Advances in Management. Diagnostics (Basel) 2020; 10:E907. [PMID: 33172025 PMCID: PMC7694636 DOI: 10.3390/diagnostics10110907] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 11/02/2020] [Accepted: 11/04/2020] [Indexed: 12/21/2022] Open
Abstract
Alagille syndrome (ALGS) is a multisystem disease characterized by cholestasis and bile duct paucity on liver biopsy in addition to variable involvement of the heart, eyes, skeleton, face, kidneys, and vasculature. The identification of JAG1 and NOTCH2 as disease-causing genes has deepened our understanding of the molecular mechanisms underlying ALGS. However, the variable expressivity of the clinical phenotype and the lack of genotype-phenotype relationships creates significant diagnostic and therapeutic challenges. In this review, we provide a comprehensive overview of the clinical characteristics and management of ALGS, and the molecular basis of ALGS pathobiology. We further describe unique diagnostic considerations that pose challenges to clinicians and outline therapeutic concepts and treatment targets that may be available in the near future.
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Affiliation(s)
- Mohammed D. Ayoub
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada;
- Department of Pediatrics, Faculty of Medicine, Rabigh Branch, King Abdulaziz University, P.O. Box 80205, Jeddah 21589, Saudi Arabia
| | - Binita M. Kamath
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada;
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12
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Intracranial Hypertension and Papilledema in a Large Cohort of Pediatric Patients With Alagille Syndrome. J Pediatr Gastroenterol Nutr 2020; 71:655-662. [PMID: 33093373 DOI: 10.1097/mpg.0000000000002883] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
AIMS AND BACKGROUND Ophthalmic abnormalities are amongst the 5 major criteria required for a diagnosis of Alagille syndrome (ALGS), of which embryotoxon, pseudopapilledema, and hypopigmented retinopathy are the most common. Papilledema with or without intracranial hypertension (ICHT) is rarely described. We report 9 pediatric cases of ALGS with bilateral papilledema, 5 of which were diagnosed with ICHT. METHODS The ophthalmic data from 85 patients with clinically and/or genetically (n = 37) proven ALGS were reviewed. The study inclusion criteria were a positive diagnosis of ALGS and availability of ophthalmic follow-up data. Ophthalmic data from 40 patients after liver transplantation (LT) for other indications were also analyzed. RESULTS Nine (13.0%) of the 69 patients meeting the inclusion criteria had papilledema. The neurological and neuroimaging results in all 9 patients were normal. These 9 patients were categorized into 4 groups: a nontransplant group (n = 1), a group with pretransplant papilledema persistent after LT (n = 2), a group with papilledema occurring after LT with spontaneous resolution (n = 1), and a group with papilledema and signs of ICHT after LT (n = 5). The patients with ICHT were treated with steroids alone (n = 1) or with acetazolamide (n = 4). A ventriculoperitoneal shunt was placed in 2 of the 5 cases because of progressive visual loss. Pseudopapilledema was present in 10 additional patients (14.5%, 10/69). One (2.5%) of the 40 patients without ALGS developed papilledema after LT. CONCLUSIONS True ICHT may be underdiagnosed in patients with ALGS. Our findings underscore the need for close ophthalmic follow-up before and after LT in these patients.
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13
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Van Hul N, Lendahl U, Andersson ER. Mouse Models for Diseases in the Cholangiocyte Lineage. Methods Mol Biol 2019; 1981:203-236. [PMID: 31016657 DOI: 10.1007/978-1-4939-9420-5_14] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cholangiopathies are an important group of liver diseases affecting the biliary system, and the purpose of this review is to describe how diseases in the biliary system can be studied in mouse models. A particular focus is placed on mouse models for Alagille syndrome, a cholangiopathy with a strong genetic link to dysfunctional Notch signaling. Recently, a number of different genetic mouse models based on various manipulations of the Notch signaling pathway have been generated to study Alagille syndrome, and we discuss the resulting phenotypes, and possible causes for the phenotypic heterogeneity among the various models. In the final section, we provide a more general discussion on how well mouse models can be expected to mimic human liver disease, as well as an outlook toward the need for new technologies that can help us to gain new insights from mouse models for liver disease.
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Affiliation(s)
- Noémi Van Hul
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - Urban Lendahl
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
| | - Emma R Andersson
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.,Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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14
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Delaney S, O'Connor G, Reardon W, Murphy SJX, Tierney S, Ryan BM, Delaney H, Doherty CP, Guiney M, Brennan P, Tobin WO, McCabe DJH. Extracranial and Intracranial Vasculopathy With "Moyamoya Phenomenon" in Association With Alagille Syndrome. Front Neurol 2019; 9:1194. [PMID: 30761079 PMCID: PMC6362309 DOI: 10.3389/fneur.2018.01194] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 12/31/2018] [Indexed: 01/21/2023] Open
Abstract
Background: Alagille syndrome (AGS) is an autosomal-dominant, multisystem disorder caused by mutations in the JAG1 gene. Case Description: A 34-year-old man was referred to our service 10 years ago with focal seizures with impaired awareness and transient slurred speech. He had a 5-year history of intermittent left monocular low-flow retinopathy. He has a family history of AGS. General examination revealed mild hypertension, aortic regurgitation, and livedo reticularis. Neurological examination was normal. Investigations: He had mild hyperlipidaemia and persistently-positive lupus anticoagulant consistent with primary anti-phospholipid syndrome. Color Doppler ultrasound revealed low velocity flow in a narrowed extracranial left internal carotid artery (ICA). MR and CT angiography revealed a diffusely narrowed extracranial and intracranial left ICA. Formal cerebral angiography confirmed severe left ICA narrowing consistent with a left ICA “vasculopathy” and moyamoya phenomenon. Transthoracic echocardiogram revealed a bicuspid aortic valve and aortic incompetence. Molecular genetic analysis identified a missense mutation (A211P) in exon 4 of the JAG1 gene, consistent with AGS. Discussion: AGS should be considered in young adults with TIAs/stroke and unexplained extracranial or intracranial vascular abnormalities, and/or moyamoya phenomenon, even in the absence of other typical phenotypic features. Gene panels should include JAG1 gene testing in similar patients.
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Affiliation(s)
- Siobhan Delaney
- Department of Neurology, The Adelaide and Meath Hospital, Dublin, Incorporating The National Children's Hospital (AMNCH)/Tallaght University Hospital, Dublin, Ireland.,Stroke Service, AMNCH/Tallaght University Hospital, Dublin, Ireland
| | - Ged O'Connor
- Department of Neurology, University Hospital Waterford, Waterford, Ireland
| | - William Reardon
- National Centre for Medical Genetics, Our Lady's Children's Hospital, Dublin, Ireland
| | - Stephen J X Murphy
- Department of Neurology, The Adelaide and Meath Hospital, Dublin, Incorporating The National Children's Hospital (AMNCH)/Tallaght University Hospital, Dublin, Ireland.,Stroke Service, AMNCH/Tallaght University Hospital, Dublin, Ireland.,Vascular Neurology Research Foundation, C/O Department of Neurology, AMNCH/Tallaght University Hospital, Dublin, Ireland
| | - Sean Tierney
- Department of Vascular Surgery, AMNCH/Tallaght University Hospital, Dublin, Ireland
| | - Barbara M Ryan
- Department of Gastroenterology, AMNCH/Tallaght University Hospital, and Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland
| | - Holly Delaney
- Department of Radiology, AMNCH/Tallaght University Hospital, Dublin, Ireland
| | - Colin P Doherty
- Department of Neurology, St James's Hospital, Dublin, Ireland
| | - Michael Guiney
- Department of Radiology, St James's Hospital, Dublin, Ireland
| | - Paul Brennan
- Department of Neuroradiology, Beaumont Hospital, Dublin, Ireland
| | - W Oliver Tobin
- Department of Neurology, The Adelaide and Meath Hospital, Dublin, Incorporating The National Children's Hospital (AMNCH)/Tallaght University Hospital, Dublin, Ireland.,Stroke Service, AMNCH/Tallaght University Hospital, Dublin, Ireland.,Department of Neurology, College of Medicine, Mayo Clinic, Rochester, MN, United States
| | - Dominick J H McCabe
- Department of Neurology, The Adelaide and Meath Hospital, Dublin, Incorporating The National Children's Hospital (AMNCH)/Tallaght University Hospital, Dublin, Ireland.,Stroke Service, AMNCH/Tallaght University Hospital, Dublin, Ireland.,Vascular Neurology Research Foundation, C/O Department of Neurology, AMNCH/Tallaght University Hospital, Dublin, Ireland.,Department of Clinical Neurosciences, Royal Free Campus, UCL Institute of Neurology, London, United Kingdom.,Irish Centre for Vascular Biology, Dublin, Ireland.,Academic Unit of Neurology, School of Medicine, Trinity College Dublin, Dublin, Ireland
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15
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Menon R, Otto EA, Kokoruda A, Zhou J, Zhang Z, Yoon E, Chen YC, Troyanskaya O, Spence JR, Kretzler M, Cebrián C. Single-cell analysis of progenitor cell dynamics and lineage specification in the human fetal kidney. Development 2018; 145:145/16/dev164038. [PMID: 30166318 PMCID: PMC6124540 DOI: 10.1242/dev.164038] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 07/30/2018] [Indexed: 12/11/2022]
Abstract
The mammalian kidney develops through reciprocal interactions between the ureteric bud and the metanephric mesenchyme to give rise to the entire collecting system and the nephrons. Most of our knowledge of the developmental regulators driving this process arises from the study of gene expression and functional genetics in mice and other animal models. In order to shed light on human kidney development, we have used single-cell transcriptomics to characterize gene expression in different cell populations, and to study individual cell dynamics and lineage trajectories during development. Single-cell transcriptome analyses of 6414 cells from five individual specimens identified 11 initial clusters of specific renal cell types as defined by their gene expression profile. Further subclustering identifies progenitors, and mature and intermediate stages of differentiation for several renal lineages. Other lineages identified include mesangium, stroma, endothelial and immune cells. Novel markers for these cell types were revealed in the analysis, as were components of key signaling pathways driving renal development in animal models. Altogether, we provide a comprehensive and dynamic gene expression profile of the developing human kidney at the single-cell level. Summary: New markers for specific cell types in the developing human kidney are identified and computational approaches infer developmental trajectories and interrogate the complex network of signaling pathways and cellular transitions.
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Affiliation(s)
- Rajasree Menon
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Edgar A Otto
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Austin Kokoruda
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jian Zhou
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.,Graduate Program in Quantitative and Computational Biology, Princeton University, Princeton, NJ 08544, USA
| | - Zidong Zhang
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.,Graduate Program in Quantitative and Computational Biology, Princeton University, Princeton, NJ 08544, USA
| | - Euisik Yoon
- Department of Electrical Engineering and Computer Science, Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yu-Chih Chen
- Department of Electrical Engineering and Computer Science, Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Olga Troyanskaya
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.,Flatiron Institute, Simons Foundation, New York, NY 10010, USA.,Department of Computer Science, Princeton University, Princeton, NJ
| | - Jason R Spence
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA .,Department of Cell and Developmental Biology, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Matthias Kretzler
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Cristina Cebrián
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109, USA
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16
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Marelli F, Persani L. Role of Jagged1-Notch pathway in thyroid development. J Endocrinol Invest 2018; 41:75-81. [PMID: 28653287 DOI: 10.1007/s40618-017-0715-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 06/12/2017] [Indexed: 10/19/2022]
Abstract
The zebrafish thyroid gland shows a unique pattern of growth. Despite the lack of a compact gland, the zebrafish thyroid tissue originates from the pharyngeal endoderm and the main genes involved in its patterning and early development are conserved between zebrafish and mammals. In recent years, the research has been focused to the search of novel candidate genes and environmental factors underlying congenital hypothyroidism. Among these, it has been demonstrated that the Notch signalling plays a central role during zebrafish thyroid development. In this review, we will provide an overview of the current knowledge of the distinct roles of the Notch signalling and of the jag1a and jag1b ligands during the different phases of thyroid organogenesis. Furthermore, we will discuss the role of JAG1 variants in congenital thyroid defects.
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Affiliation(s)
- F Marelli
- Department of Clinical and Community Sciences, University of Milan, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149, Milan, Italy
| | - L Persani
- Department of Clinical and Community Sciences, University of Milan, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149, Milan, Italy.
- Laboratorio di Ricerche Endocrino-Metaboliche, IRCCS Istituto Auxologico Italiano, Milan, Italy.
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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18
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Receveur A, Brisset S, Martinovic J, Bazin A, Lhomann L, Colmant C, Pineau D, Gautier V, Tosca L, Tachdjian G. Prenatal diagnosis of isochromosome 20q in a fetus with vertebral anomaly and rocker-bottom feet. Taiwan J Obstet Gynecol 2017; 56:677-680. [DOI: 10.1016/j.tjog.2017.08.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2017] [Indexed: 11/26/2022] Open
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19
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Guan Y, Xu D, Garfin PM, Ehmer U, Hurwitz M, Enns G, Michie S, Wu M, Zheng M, Nishimura T, Sage J, Peltz G. Human hepatic organoids for the analysis of human genetic diseases. JCI Insight 2017; 2:94954. [PMID: 28878125 PMCID: PMC5621886 DOI: 10.1172/jci.insight.94954] [Citation(s) in RCA: 143] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 07/25/2017] [Indexed: 12/31/2022] Open
Abstract
We developed an in vitro model system where induced pluripotent stem cells (iPSCs) differentiate into 3-dimensional human hepatic organoids (HOs) through stages that resemble human liver during its embryonic development. The HOs consist of hepatocytes, and cholangiocytes, which are organized into epithelia that surround the lumina of bile duct-like structures. The organoids provide a potentially new model for liver regenerative processes, and were used to characterize the effect of different JAG1 mutations that cause: (a) Alagille syndrome (ALGS), a genetic disorder where NOTCH signaling pathway mutations impair bile duct formation, which has substantial variability in its associated clinical features; and (b) Tetralogy of Fallot (TOF), which is the most common form of a complex congenital heart disease, and is associated with several different heritable disorders. Our results demonstrate how an iPSC-based organoid system can be used with genome editing technologies to characterize the pathogenetic effect of human genetic disease-causing mutations.
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Affiliation(s)
| | | | | | - Ursula Ehmer
- Department of Pediatrics
- Department of Genetics, and
| | | | | | - Sara Michie
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
| | | | | | - Toshihiko Nishimura
- Department of Anesthesia
- Center for the Advancement of Health and Bioscience, Sunnyvale, California, USA
- Central Institute for Experimental Animals, Tokyo, Japan
| | - Julien Sage
- Department of Pediatrics
- Department of Genetics, and
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20
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Huang T, Yang G, Dang X, Ao F, Li J, He Y, Tang Q, He Q. Implementing targeted region capture sequencing for the clinical detection of Alagille syndrome: An efficient and cost-effective method. Mol Med Rep 2017; 16:6876-6881. [DOI: 10.3892/mmr.2017.7429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 02/21/2017] [Indexed: 11/05/2022] Open
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21
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Prenatal exposure to environmental factors and congenital limb defects. ACTA ACUST UNITED AC 2016; 108:243-273. [DOI: 10.1002/bdrc.21140] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 09/29/2016] [Indexed: 12/26/2022]
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22
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Exocrine pancreatic function in children with Alagille syndrome. Sci Rep 2016; 6:35229. [PMID: 27748459 PMCID: PMC5066201 DOI: 10.1038/srep35229] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 08/25/2016] [Indexed: 11/25/2022] Open
Abstract
Alagille syndrome (AGS) is often associated with symptoms of maldigestion, such as steatorrhea, hypotrophy and growth retardation. Exocrine pancreatic insufficiency was proposed as the underlying cause. We aimed to assess the exocrine pancreatic function with the use of different methods in AGS patients. Concentrations of fecal elastase-1 (FE1) and fecal lipase (FL) activities were measured in 33 children with AGS. The C-mixed triglyceride breath test (MTBT) in a subgroup comprising 15 patients. In all patients studied, FE1 concentrations and FL activities were normal. Abnormal MTBT results were documented in 4 (26.7%) patients. The FE1 and FL levels in MTBT-positive and MTBT-negative children did not differ. The results of this research do not confirm the presence of exocrine pancreatic dysfunction in AGS patients. Routine screening for exocrine pancreatic insufficiency of this group of patients is not necessary.
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CT-defined phenotype of pulmonary artery stenoses in Alagille syndrome. Pediatr Radiol 2016; 46:1120-7. [PMID: 27041277 DOI: 10.1007/s00247-016-3580-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2015] [Revised: 01/18/2016] [Accepted: 02/09/2016] [Indexed: 10/22/2022]
Abstract
BACKGROUND Alagille syndrome is a rare disorder commonly associated with pulmonary artery stenosis. Studies exist discussing the cardiovascular sequela but no consistent phenotype, or pattern of pulmonary artery stenosis, has been described. OBJECTIVE The objective of this study was to characterize the distribution and severity of pulmonary artery stenosis in patients with Alagille syndrome based on computed tomography angiography. MATERIALS AND METHODS A retrospective chart review identified patients with Alagille syndrome who had undergone CT angiography. Pulmonary trunk (MPA), left main pulmonary artery (LPA) and right main pulmonary artery (RPA) diameters in Alagille patients were compared with those from matched control subjects. Stenoses at lobar and segmental pulmonary arteries were categorized as: Grade 1 (<33% stenosis), Grade 2 (33-66% stenosis) or Grade 3 (>66% stenosis). Involvement among the different lung regions was then compared. RESULTS Fifteen patients ages 6 months to 17 years were identified; one had surgical augmentation of the central pulmonary arteries and was excluded from the central (main, right and left) pulmonary artery analysis. The proximal LPA and RPA, but not the MPA, were significantly smaller than those of the control subjects (P<0.01). The proximal LPA was significantly smaller than the proximal RPA (P<0.01) in the Alagille group (0.55 LPA:RPA ratio). Within the Alagille group, 75% of the lobar and segmental branches showed mild or no stenoses (Grade 1), 17% showed moderate stenosis (Grade 2) and 8% showed severe stenosis (Grade 3). While not statistically significant, the right lung demonstrated a greater percentage of Grades 2 and 3 stenoses (28%, right vs. 20% left, P=0.1). The right middle and lingula lobes of both lungs showed more Grade 2 and 3 stenoses (33% upper/middle vs. 18% lower, P<0.01). CONCLUSION We describe a common pattern pulmonary artery stenosis in Alagille patients consisting of severe proximal LPA stenosis, heavy involvement of the lobar and segmental branches (more often right than left), and a greater involvement of the upper lobes. Knowledge of this phenotypic pattern can help in the diagnosis of Alagille syndrome in patients presenting with pulmonary artery stenosis.
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González Pastor S, Montraveta Querol M, Del Alcazar Muñoz R, Ojanguren Sabán MI, Pintos Morell G, Quintero Bernabeu J, Juamperez Goñi J, Sala Llinas M. Alagille syndrome associated with intestinal atresia. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 39:667-668. [PMID: 26596367 DOI: 10.1016/j.gastrohep.2015.09.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 09/09/2015] [Accepted: 09/17/2015] [Indexed: 11/16/2022]
Affiliation(s)
- Sara González Pastor
- Servicio de Pediatría y Anatomía Patológica, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, España.
| | - Montserrat Montraveta Querol
- Servicio de Pediatría y Anatomía Patológica, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, España
| | - Ricard Del Alcazar Muñoz
- Servicio de Pediatría y Anatomía Patológica, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, España
| | - Maria Isabel Ojanguren Sabán
- Servicio de Pediatría y Anatomía Patológica, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, España
| | - Guillem Pintos Morell
- Servicio de Pediatría y Anatomía Patológica, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, España
| | - Jesus Quintero Bernabeu
- Servicio de Pediatría y Anatomía Patológica, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, España
| | - Javier Juamperez Goñi
- Servicio de Pediatría y Anatomía Patológica, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, España
| | - Margarita Sala Llinas
- Servicio de Pediatría y Anatomía Patológica, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, España
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25
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Jagged1 (JAG1): Structure, expression, and disease associations. Gene 2015; 576:381-4. [PMID: 26548814 DOI: 10.1016/j.gene.2015.10.065] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 10/22/2015] [Accepted: 10/25/2015] [Indexed: 01/29/2023]
Abstract
Jagged1 (JAG1) is one of the 5 cell surface ligands that functions primarily in the highly conserved Notch signaling pathway. Notch signaling plays a critical role in cellular fate determination and is active throughout development and across many organ systems. The classic JAG1-NOTCH interaction leads to a cascade of proteolytic cleavages resulting in the NOTCH intracellular domain being transported into the nucleus where it functions to activate downstream transcription of target genes. JAG1 mutations have been associated with several disorders including the multi-system dominant disorder Alagille syndrome, and some cases of tetralogy of Fallot (although these may represent variable expressivity of Alagille syndrome). In addition, variations in JAG1 have been found to be associated with multiple types of cancer including breast cancer and adrenocortical carcinoma. Alagille syndrome, which primarily affects the liver, heart, skeleton, eye, face, kidney and vasculature is caused by loss of function mutations in JAG1, demonstrating that haploinsufficiency for JAG1 is disease causing, at least in these tissues. Expression and conditional gene knockout studies of JAG1 (Jag1) have correlated with tissue-specific disease phenotypes and have provided insight into both disease pathogenesis and human development.
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26
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Démurger F, Ichkou A, Mougou-Zerelli S, Le Merrer M, Goudefroye G, Delezoide AL, Quélin C, Manouvrier S, Baujat G, Fradin M, Pasquier L, Megarbané A, Faivre L, Baumann C, Nampoothiri S, Roume J, Isidor B, Lacombe D, Delrue MA, Mercier S, Philip N, Schaefer E, Holder M, Krause A, Laffargue F, Sinico M, Amram D, André G, Liquier A, Rossi M, Amiel J, Giuliano F, Boute O, Dieux-Coeslier A, Jacquemont ML, Afenjar A, Van Maldergem L, Lackmy-Port-Lis M, Vincent-Delorme C, Chauvet ML, Cormier-Daire V, Devisme L, Geneviève D, Munnich A, Viot G, Raoul O, Romana S, Gonzales M, Encha-Razavi F, Odent S, Vekemans M, Attie-Bitach T. New insights into genotype-phenotype correlation for GLI3 mutations. Eur J Hum Genet 2014; 23:92-102. [PMID: 24736735 DOI: 10.1038/ejhg.2014.62] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 01/20/2014] [Accepted: 03/13/2014] [Indexed: 01/15/2023] Open
Abstract
The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.
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Affiliation(s)
- Florence Démurger
- Service de Génétique Clinique, CLAD-Ouest, Hôpital Sud, Rennes, France
| | - Amale Ichkou
- Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris (AP-HP), Paris, France
| | - Soumaya Mougou-Zerelli
- 1] Inserm U1163, Hôpital Necker-Enfants Malades, Paris, France [2] Service de Cytogénétique et Biologie de la Reproduction, CHU Farhat Hached, Sousse, Tunisia
| | | | - Géraldine Goudefroye
- Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris (AP-HP), Paris, France
| | | | - Chloé Quélin
- Service de Génétique Clinique, CLAD-Ouest, Hôpital Sud, Rennes, France
| | - Sylvie Manouvrier
- Service de Génétique Clinique, CLAD-NdF, CHRU de Lille, Lille, France
| | - Geneviève Baujat
- 1] Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris (AP-HP), Paris, France [2] Inserm U1163, Hôpital Necker-Enfants Malades, Paris, France [3] Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Paris, France
| | - Mélanie Fradin
- Service de Génétique Clinique, CLAD-Ouest, Hôpital Sud, Rennes, France
| | - Laurent Pasquier
- Service de Génétique Clinique, CLAD-Ouest, Hôpital Sud, Rennes, France
| | - André Megarbané
- Unité de Génétique Médicale, Faculté de Médecine, Université St Joseph, Beirut, Lebanon
| | - Laurence Faivre
- Centre de Génétique, Hôpital d'enfants, CHU de Dijon, Dijon, France
| | - Clarisse Baumann
- Département de Génétique, Hôpital Robert Debré, AP-HP, Paris, France
| | - Sheela Nampoothiri
- Department of Pediatric Genetics, Amrita Institute of Medical Sciences, Kerala, India
| | - Joëlle Roume
- Unité de Génétique Médicale, CH Poissy St-Germain-en-Laye, Poissy, France
| | - Bertrand Isidor
- Service de Génétique Médicale, Unité de Génétique Clinique, CLAD-Ouest, CHU de Nantes, Nantes, France
| | - Didier Lacombe
- Service de Génétique Médicale, CHU de Bordeaux, Bordeaux, France
| | | | - Sandra Mercier
- Service de Génétique Médicale, Unité de Génétique Clinique, CLAD-Ouest, CHU de Nantes, Nantes, France
| | - Nicole Philip
- Département de Génétique Médicale, Hôpital d'Enfants de La Timone, Marseille, France
| | - Elise Schaefer
- Service de Génétique Médicale, CHU de Strasbourg, Strasbourg, France
| | - Muriel Holder
- Service de Génétique Clinique, CLAD-NdF, CHRU de Lille, Lille, France
| | - Amanda Krause
- Division de Génétique Humaine, Hospital St Hillbrow, Johannesburg, South Africa
| | - Fanny Laffargue
- Service de Génétique Médicale, CHU Estaing, Clermont-Ferrand, France
| | - Martine Sinico
- Service d'Anatomie Pathologique, CH Intercommunal de Créteil, Créteil, France
| | - Daniel Amram
- Unité de Génétique Clinique, CH Intercommunal de Créteil, Créteil, France
| | - Gwenaelle André
- Service d'Anatomie Pathologique, CHU Pellegrin, Bordeaux, France
| | - Alain Liquier
- Laboratoire de Cytogénétique Bioffice, Bordeaux, France
| | | | - Jeanne Amiel
- 1] Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris (AP-HP), Paris, France [2] Inserm U1163, Hôpital Necker-Enfants Malades, Paris, France [3] Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Paris, France
| | - Fabienne Giuliano
- Service de Génétique Médicale, Hôpital de l'Archet II, CHU de Nice, France
| | - Odile Boute
- Service de Génétique Clinique, CLAD-NdF, CHRU de Lille, Lille, France
| | | | | | - Alexandra Afenjar
- 1] Service de Génétique, Hôpital Pitié Salpêtrière, Paris, France [2] Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Hôpital Trousseau, AP-HP, Paris, France
| | | | | | | | - Marie-Liesse Chauvet
- 1] Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris (AP-HP), Paris, France [2] Inserm U1163, Hôpital Necker-Enfants Malades, Paris, France
| | - Valérie Cormier-Daire
- 1] Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris (AP-HP), Paris, France [2] Inserm U1163, Hôpital Necker-Enfants Malades, Paris, France [3] Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Paris, France
| | - Louise Devisme
- Institut de Pathologie, Centre de Biologie-Pathologie, CHRU de Lille, France
| | - David Geneviève
- Département de Génétique Médicale, CHU de Montpellier, France
| | - Arnold Munnich
- 1] Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris (AP-HP), Paris, France [2] Inserm U1163, Hôpital Necker-Enfants Malades, Paris, France [3] Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Paris, France
| | - Géraldine Viot
- Unité de Génétique, Maternité Port-Royal, Hôpital Cochin, AP-HP, Paris, France
| | - Odile Raoul
- Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris (AP-HP), Paris, France
| | - Serge Romana
- 1] Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris (AP-HP), Paris, France [2] Inserm U1163, Hôpital Necker-Enfants Malades, Paris, France [3] Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Paris, France
| | - Marie Gonzales
- Service de Génétique et d'Embryologie Médicales, Hôpital Armand Trousseau, AP-HP, Paris, France
| | - Ferechte Encha-Razavi
- 1] Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris (AP-HP), Paris, France [2] Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Paris, France
| | - Sylvie Odent
- Service de Génétique Clinique, CLAD-Ouest, Hôpital Sud, Rennes, France
| | - Michel Vekemans
- 1] Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris (AP-HP), Paris, France [2] Inserm U1163, Hôpital Necker-Enfants Malades, Paris, France [3] Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Paris, France
| | - Tania Attie-Bitach
- 1] Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris (AP-HP), Paris, France [2] Inserm U1163, Hôpital Necker-Enfants Malades, Paris, France [3] Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Paris, France
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Berniczei-Royko A, Chałas R, Mitura I, Nagy K, Prussak E. Medical and dental management of Alagille syndrome: a review. Med Sci Monit 2014; 20:476-80. [PMID: 24658020 PMCID: PMC3972053 DOI: 10.12659/msm.890577] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Alagille syndrome is a rare, autosomal, complex, dominant disorder associated with dysfunction of the liver, heart, skeleton, and eyes, as well as characteristic facial appearance. It is associated with the defect in component of the Notch signalling pathway. Here, we review the main features of Alagille syndrome with special focus on oro-facial manifestations like prominent forehead, moderate hypertelorism with deep-set eyes, a saddle or straight nose with a flattened, bulbous tip, and large ears. The article is based on the most recent and significant literature available from the Medline database. Contrary to healthy children, patients with Alagille syndrome have many problems, depending on several factors like the severity of cholestasis and scarring in the liver, heart or lung problems, presence of infections, or other problems related to poor nutrition that can manifest in their oral cavity in the dental and periodontal tissues, as well as oral mucosa. From the dentist’s view, the most important elements are careful observation, accurate diagnosis, and planned management of such patients, especially during the patient’s formative years, to prevent complications. Aggressive preventive oral care and consultations with medical specialists before any invasive procedure are obligatory. All this can improve quality of life in patients with Alagille syndrome.
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Affiliation(s)
| | - Renata Chałas
- Department of Conservative Dentistry and Endodontics, Medical University of Lublin, Lublin, Poland
| | - Iwona Mitura
- Orthodontic Clinic, Dental Clinical Center, Medical University of Lublin, Lublin, Poland
| | - Katalin Nagy
- Department of Oral Surgery, University of Szeged, Szeged, Hungary
| | - Elżbieta Prussak
- Department of Management in Health Care, University of Medical Sciences, Poznań, Poland
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Yamamura H, Yamamura A, Ko EA, Pohl NM, Smith KA, Zeifman A, Powell FL, Thistlethwaite PA, Yuan JXJ. Activation of Notch signaling by short-term treatment with Jagged-1 enhances store-operated Ca(2+) entry in human pulmonary arterial smooth muscle cells. Am J Physiol Cell Physiol 2014; 306:C871-8. [PMID: 24573085 DOI: 10.1152/ajpcell.00221.2013] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Notch signaling plays a critical role in controlling proliferation and differentiation of pulmonary arterial smooth muscle cells (PASMC). Upregulated Notch ligands and Notch3 receptors in PASMC have been reported to promote the development of pulmonary vascular remodeling in patients with pulmonary arterial hypertension (PAH) and in animals with experimental pulmonary hypertension. Activation of Notch receptors by their ligands leads to the cleavage of the Notch intracellular domain (NICD) to the cytosol by γ-secretase; NICD then translocates into the nucleus to regulate gene transcription. In this study, we examined whether short-term activation of Notch functionally regulates store-operated Ca(2+) entry (SOCE) in human PASMC. Treatment of PASMC with the active fragment of human Jagged-1 protein (Jag-1) for 15-60 min significantly increased the amplitude of SOCE induced by passive deletion of Ca(2+) from the intracellular stores, the sarcoplasmic reticulum (SR). The Jag-1-induced enhancement of SOCE was time dependent: the amplitude was maximized at 30 min of treatment with Jag-1, which was closely correlated with the time course of Jag-1-mediated increase in NICD protein level. The scrambled peptide of Jag-1 active fragment had no effect on SOCE. Inhibition of γ-secretase by N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) significantly attenuated the Jag-1-induced augmentation of SOCE. In addition to the short-term effect, prolonged treatment of PASMC with Jag-1 for 48 h also markedly enhanced the amplitude of SOCE. These data demonstrate that short-term activation of Notch signaling enhances SOCE in PASMC; the NICD-mediated functional interaction with store-operated Ca(2+) channels (SOC) may be involved in the Jag-1-mediated enhancement of SOCE in human PASMC.
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Affiliation(s)
- Hisao Yamamura
- Department of Medicine, Institute for Personalized Respiratory Medicine, Department of Pharmacology; Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois
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Liu WH, Ren LN, Chen T, Liu LY, Tang LJ. Stages based molecular mechanisms for generating cholangiocytes from liver stem/progenitor cells. World J Gastroenterol 2013; 19:7032-7041. [PMID: 24222945 PMCID: PMC3819537 DOI: 10.3748/wjg.v19.i41.7032] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 09/01/2013] [Accepted: 09/15/2013] [Indexed: 02/06/2023] Open
Abstract
Except for the most organized mature hepatocytes, liver stem/progenitor cells (LSPCs) can differentiate into many other types of cells in the liver including cholangiocytes. In addition, LSPCs are demonstrated to be able to give birth to other kinds of extra-hepatic cell types such as insulin-producing cells. Even more, under some bad conditions, these LSPCs could generate liver cancer stem like cells (LCSCs) through malignant transformation. In this review, we mainly concentrate on the molecular mechanisms for controlling cell fates of LSPCs, especially differentiation of cholangiocytes, insulin-producing cells and LCSCs. First of all, to certificate the cell fates of LSPCs, the following three features need to be taken into account to perform accurate phenotyping: (1) morphological properties; (2) specific markers; and (3) functional assessment including in vivo transplantation. Secondly, to promote LSPCs differentiation, systematical attention should be paid to inductive materials (such as growth factors and chemical stimulators), progressive materials including intracellular and extracellular signaling pathways, and implementary materials (such as liver enriched transcriptive factors). Accordingly, some recommendations were proposed to standardize, optimize, and enrich the effective production of cholangiocyte-like cells out of LSPCs. At the end, the potential regulating mechanisms for generation of cholangiocytes by LSPCs were carefully analyzed. The differentiation of LSPCs is a gradually progressing process, which consists of three main steps: initiation, progression and accomplishment. It's the unbalanced distribution of affecting materials in each step decides the cell fates of LSPCs.
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Renal involvement and the role of Notch signalling in Alagille syndrome. Nat Rev Nephrol 2013; 9:409-18. [PMID: 23752887 DOI: 10.1038/nrneph.2013.102] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Alagille syndrome is an autosomal dominant disorder with variable multisystem organ involvement that is caused by mutations in one of two genes in the Notch signalling pathway, JAG1 or NOTCH2. Alagille syndrome is characterized by bile duct paucity, along with at least three of the following features: cholestasis, cardiac defects, skeletal abnormalities, ocular abnormalities and characteristic facies. However, the clinical features of Alagille syndrome are highly variable, and children or adults may also present with predominantly renal findings and little or no hepatic involvement. Renal involvement occurs in 40% of JAG1-mutation-positive individuals. Renal insufficiency is common and has been specifically reported in children with Alagille syndrome who have end-stage liver disease. The role of NOTCH2 and JAG1 in formation of proximal nephron structures and podocytes might explain the observed phenotypes of renal dysplasia and proteinuria in patients with Alagille syndrome, and renal tubular acidosis may be the result of JAG1 expression in the collecting ducts. Renal vascular hypertension in patients with Alagille syndrome is explained by the widespread vasculopathy and the role of Notch signalling in vascular development. Increased awareness of Alagille syndrome amongst nephrologists may lead to more diagnoses of Alagille syndrome in patients with apparently isolated renal disease.
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Furubo S, Sato Y, Harada K, Nakanuma Y. Roles of myofibroblasts and notch and hedgehog signaling pathways in the formation of intrahepatic bile duct lesions in polycystic kidney rats. Pediatr Dev Pathol 2013; 16:177-90. [PMID: 23331119 DOI: 10.2350/12-11-1267-oa.1] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Polycystic kidney (PCK) rats, an animal model of Caroli's disease, show a dilatation of intrahepatic bile ducts (IHBD) called "ductal plate malformation." Mesenchymal cells and the Notch and Hedgehog signaling pathways in portal tracts are reportedly involved in the normal development of IHBD, although there have been no studies on the roles of these signaling pathways in PCK rats. We immunohistochemically examined the expression of the molecules related to these signaling pathways in portal tracts. All molecules related to these signaling pathways expressed in portal tracts in Sprague Dawley (SD) rats (control) were also expressed in PCK rats. Mesenchymal cells (myofibroblasts) were frequently found in the connective tissue of portal tracts of 20 embryonic-day-old (E20D), 1-day-old (1D), and 1-week-old (1W) SD and PCK rats and were abundant in PCK rats. Interestingly, myofibroblasts almost disappeared at in both strains of 3W rats. Jagged1 was expressed in mesenchymal cells in portal tracts and was abundant in PCK rats. Double immunostaining showed that Jagged1-positive cells were myofibroblasts. Notch2 and HES1 were expressed in cholangiocytes of the bile ducts of both rats. Sonic Hedgehog was similarly expressed in the bile ducts of both rats. A well-balanced and time-sequential expression of the Notch and Hedgehog family in portal tracts might be essential for the normal development of IHBD in E20D to 1W SD rats, and an imbalanced interaction of these molecules, particularly increased Jagged1 expression in periductal and periportal myofibroblasts and Notch2 expressed in cholangiocytes, may be involved in the formation of bile duct lesions in PCK rats.
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Affiliation(s)
- Shinichi Furubo
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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Copeland E, Renault N, Renault M, Dyack S, Bulman DE, Bedard K, Otley A, Magee F, Acott P, Greer WL. Novel splice-site mutation in ATP8B1 results in atypical progressive familial intrahepatic cholestasis type 1. J Gastroenterol Hepatol 2013; 28:560-4. [PMID: 23033845 DOI: 10.1111/j.1440-1746.2012.07290.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/11/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Our objective was to identify the molecular genetic basis of an Alagille-like condition not linked to JAG1 or NOTCH2 in two related sibships. METHODS Because of common ancestry, and an autosomal recessive mode of inheritance, it was hypothesized that all affected and no unaffected individuals would be homozygous for the same haplotype in the region of the causative gene. Single nucleotide polymorphism arrays were therefore used to genotype 3 affected individuals from two sibships, their mothers and four unaffected siblings, to identify regions of homozygosity. Genes within the largest regions were prioritized and sequenced for mutations. Mutant RNA transcripts were also sequenced. RESULTS A novel splice acceptor site mutation in the ATP8B1 gene was identified (a G-C preceding exon 16 resulting in a 4 bp deletion and frameshift from the 5' end of exon 16). This result was unexpected because ATP8B1 mutations are associated with progressive familial intrahepatic cholestasis type 1 (PFIC1). Intrahepatic bile duct paucity, cardiac anomalies, renal tubular acidosis and hypothyroidism led to an initial diagnosis of Alagille syndrome. However, in retrospect, abnormal sweat chloride, normal gamma-glutamyl transferase, normal to low cholesterol, and an autosomal recessive mode of inheritance were consistent with PFIC1. Renal tubular acidosis, hypothyroidism and cardiac anomalies have not previously been associated with PFIC1. CONCLUSION This work expands the phenotypic spectrum of PFIC1, and highlights the overlap in clinical phenotype between Alagille syndrome and PFIC1. Knowledge of the causative mutation allows for carrier testing and prenatal diagnosis in this community.
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Affiliation(s)
- Emily Copeland
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
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Porazzi P, Marelli F, Benato F, de Filippis T, Calebiro D, Argenton F, Tiso N, Persani L. Disruptions of global and JAGGED1-mediated notch signaling affect thyroid morphogenesis in the zebrafish. Endocrinology 2012; 153:5645-58. [PMID: 23008514 DOI: 10.1210/en.2011-1888] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The mechanisms underlying the early steps of thyroid development are largely unknown. In search for novel candidate genes implicated in thyroid function, we performed a gene expression analysis on thyroid cells revealing that TSH regulates the expression of several elements of the Notch pathway, including the ligand Jagged1. Because the Notch pathway is involved in cell-fate determination of several foregut-derived endocrine tissues, we tested its contribution in thyroid development using the zebrafish, a teleost model recapitulating the mammalian molecular events during thyroid development. Perturbing the Notch signaling (e.g. mib mutants, γ-secretase inhibition, or Notch intracellular domain overexpression), we obtained evidence that this pathway has a biological role during the earlier phases of thyroid primordium induction, limiting the number of cells that proceed to a specialized fate and probably involving actions from surrounding tissues. Moreover, we were able to confirm the expression of Jagged1 during different phases of zebrafish thyroid development, as well as in mouse and human thyroid tissues. The two orthologues to the single jagged1 gene (JAG1) in humans, jag1a and jag1b, are expressed with different spatiotemporal patterns in the developing zebrafish thyroid. Both jag1a and jag1b morphants, as well as jag1b mutant fish line, display thyroid hypoplasia and impaired T(4) production; this thyroid phenotype was rescued by coinjection of human JAG1 mRNA. In conclusion, Notch pathway is involved in the early steps of thyroid morphogenesis, and Jagged1-Notch signal is required for zebrafish thyroid development and function. Thus, genetic alterations affecting the Notch pathway may confer susceptibility for thyroid dysgenesis.
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Affiliation(s)
- Patrizia Porazzi
- Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy
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Hofmann JJ, Briot A, Enciso J, Zovein AC, Ren S, Zhang ZW, Radtke F, Simons M, Wang Y, Iruela-Arispe ML. Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome. Development 2012; 139:4449-60. [PMID: 23095891 DOI: 10.1242/dev.084871] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The Notch signaling pathway is an important contributor to the development and homeostasis of the cardiovascular system. Not surprisingly, mutations in Notch receptors and ligands have been linked to a variety of hereditary diseases that impact both the heart and the vasculature. In particular, mutations in the gene encoding the human Notch ligand jagged 1 result in a multisystem autosomal dominant disorder called Alagille syndrome, which includes tetralogy of Fallot among its more severe cardiac pathologies. Jagged 1 is expressed throughout the developing embryo, particularly in endothelial cells. Here, we demonstrate that endothelial-specific deletion of Jag1 leads to cardiovascular defects in both embryonic and adult mice that are reminiscent of those in Alagille syndrome. Mutant mice display right ventricular hypertrophy, overriding aorta, ventricular septal defects, coronary vessel abnormalities and valve defects. Examination of mid-gestational embryos revealed that the loss of Jag1, similar to the loss of Notch1, disrupts endothelial-to-mesenchymal transition during endocardial cushion formation. Furthermore, adult mutant mice exhibit cardiac valve calcifications associated with abnormal matrix remodeling and induction of bone morphogenesis. This work shows that the endothelium is responsible for the wide spectrum of cardiac phenotypes displayed in Alagille Syndrome and it demonstrates a crucial role for Jag1 in valve morphogenesis.
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Affiliation(s)
- Jennifer J Hofmann
- Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA
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Holman EC, Campbell LJ, Hines J, Crews CM. Microarray analysis of microRNA expression during axolotl limb regeneration. PLoS One 2012; 7:e41804. [PMID: 23028429 PMCID: PMC3441534 DOI: 10.1371/journal.pone.0041804] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2011] [Accepted: 06/29/2012] [Indexed: 12/21/2022] Open
Abstract
Among vertebrates, salamanders stand out for their remarkable capacity to quickly regrow a myriad of tissues and organs after injury or amputation. The limb regeneration process in axolotls (Ambystoma mexicanum) has been well studied for decades at the cell-tissue level. While several developmental genes are known to be reactivated during this epimorphic process, less is known about the role of microRNAs in urodele amphibian limb regeneration. Given the compelling evidence that many microRNAs tightly regulate cell fate and morphogenetic processes through development and adulthood by modulating the expression (or re-expression) of developmental genes, we investigated the possibility that microRNA levels change during limb regeneration. Using two different microarray platforms to compare the axolotl microRNA expression between mid-bud limb regenerating blastemas and non-regenerating stump tissues, we found that miR-21 was overexpressed in mid-bud blastemas compared to stump tissue. Mature A. mexicanum (“Amex”) miR-21 was detected in axolotl RNA by Northern blot and differential expression of Amex-miR-21 in blastema versus stump was confirmed by quantitative RT-PCR. We identified the Amex Jagged1 as a putative target gene for miR-21 during salamander limb regeneration. We cloned the full length 3′UTR of Amex-Jag1, and our in vitro assays demonstrated that its single miR-21 target recognition site is functional and essential for the response of the Jagged1 gene to miR-21 levels. Our findings pave the road for advanced in vivo functional assays aimed to clarify how microRNAs such as miR-21, often linked to pathogenic cell growth, might be modulating the redeployment of developmental genes such as Jagged1 during regenerative processes.
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Affiliation(s)
- Edna C. Holman
- Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America
| | - Leah J. Campbell
- Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America
| | - John Hines
- Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America
| | - Craig M. Crews
- Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut, United States of America
- Department of Chemistry, Yale University, New Haven, Connecticut, United States of America
- Department of Pharmacology, Yale University, New Haven, Connecticut, United States of America
- * E-mail:
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Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T, Forbes SJ. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med 2012; 18:572-9. [PMID: 22388089 PMCID: PMC3364717 DOI: 10.1038/nm.2667] [Citation(s) in RCA: 601] [Impact Index Per Article: 46.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Accepted: 01/09/2012] [Indexed: 12/14/2022]
Abstract
During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during chronic liver injury is promoted.
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Affiliation(s)
- Luke Boulter
- Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
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Wang H, Wang X, Li Q, Chen S, Liu L, Wei Z, Wang L, Liu Y, Zhao X, He L, Wang J, Xing Q. Analysis of JAG1 gene variant in Chinese patients with Alagille syndrome. Gene 2012; 499:191-3. [PMID: 22405927 DOI: 10.1016/j.gene.2012.02.038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Revised: 02/17/2012] [Accepted: 02/20/2012] [Indexed: 10/28/2022]
Abstract
Alagille syndrome (AGS) is an autosomal dominant disorder characterized by bile duct paucity. It can be caused by variations in the JAG1 gene encoding a protein of Notch ligand and by variations in the NOTCH2 gene encoding a Notch receptor. In this study we identified 15 different JAG1 gene variations in 17 Chinese patients, nine of which were novel alterations including c.766G > T, c.819delC, c.826delT, c.3099_3100delCA, c.1323_1326delCTGG, c.1771_1775delGTGCGinsT, c.1868delG, c. 2791_2792insA and c.866delG. These alterations were located in the extracellular domain of JAG1, in particular in the DSL and EGF-like repeat domain. All the specific variations in five inheritance cases investigated were de novo. Furthermore, no sequence variation of NOTCH2 was detected in JAG1 alteration negative patients.
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Affiliation(s)
- Honglian Wang
- Children's Hospital of Fudan University, Shanghai, China; Institute of Biomedical Sciences, Fudan University, Shanghai, China
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Steg AD, Katre AA, Goodman B, Han HD, Nick AM, Stone RL, Coleman RL, Alvarez RD, Lopez-Berestein G, Sood AK, Landen CN. Targeting the notch ligand JAGGED1 in both tumor cells and stroma in ovarian cancer. Clin Cancer Res 2011; 17:5674-85. [PMID: 21753153 PMCID: PMC3166981 DOI: 10.1158/1078-0432.ccr-11-0432] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE Jagged1, a Notch ligand, is expressed on both tumor epithelial and endothelial cells and therefore may be amenable to dual targeting of the tumor stroma and malignant cell compartments of the tumor microenvironment. EXPERIMENTAL DESIGN We describe in vitro effects of targeting of Jagged1 on ovarian cancer cells and in vivo effects of independent targeting of stromal and malignant cell Jagged1 using species-specific human or murine siRNA constructs incorporated into chitosan nanoparticles and delivered intravenously in an orthotopic mouse model. RESULTS Jagged1 expression was prominent in SKOV3ip1 and IGROV-AF1, and significantly overexpressed in SKOV3TRip2, a taxane-resistant SKOV3 subclone. Jagged1 silencing with siRNA decreased cell viability and reversed taxane chemoresistance. In two different orthotopic ovarian cancer models, treatment with anti-human Jagged1 siRNA-CH reduced growth by 54.4% to 58.3% and with anti-murine Jagged1 siRNA-CH reduced growth by 41.7% to 48.8%. The combination of both species-specific constructs reduced tumor weight by 87.5% to 93.1% and sensitized SKOV3TRip2 tumors to docetaxel in vivo. Tumors showed reduced microvessel density with anti-murine Jagged1 constructs and decreased proliferation with anti-human Jagged1 siRNAs-CH. In addition, we show that Jagged1 downregulation does not sensitize cells to taxanes through a reduction in MDR1 expression, but at least in part by cross-talk with the GLI2 mediator of the Hedgehog pathway. CONCLUSIONS Jagged1 plays dual roles in cancer progression through an angiogenic function in tumor endothelial cells and through proliferation and chemoresistance in tumor cells. Dual inhibition represents an attractive therapeutic strategy for ovarian and potentially other malignancies.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis
- Animals
- Antineoplastic Agents/pharmacology
- Apoptosis/drug effects
- Bridged-Ring Compounds/pharmacology
- Calcium-Binding Proteins/genetics
- Calcium-Binding Proteins/metabolism
- Cell Line, Tumor
- Cell Proliferation
- Docetaxel
- Drug Resistance, Neoplasm
- Endothelial Cells/metabolism
- Epithelial Cells/metabolism
- Female
- Hedgehog Proteins/genetics
- Hedgehog Proteins/metabolism
- Humans
- Intercellular Signaling Peptides and Proteins/genetics
- Intercellular Signaling Peptides and Proteins/metabolism
- Jagged-1 Protein
- Kruppel-Like Transcription Factors/genetics
- Kruppel-Like Transcription Factors/metabolism
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice
- Molecular Targeted Therapy
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/genetics
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Ovarian Neoplasms/blood supply
- Ovarian Neoplasms/drug therapy
- Ovarian Neoplasms/metabolism
- Ovarian Neoplasms/pathology
- RNA Interference
- RNA, Small Interfering
- Receptors, Notch/genetics
- Receptors, Notch/metabolism
- Serrate-Jagged Proteins
- Stromal Cells
- Taxoids/pharmacology
- Transcription Factors/biosynthesis
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Zinc Finger Protein GLI1
- Zinc Finger Protein Gli2
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Affiliation(s)
- Adam D. Steg
- Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Ashwini A. Katre
- Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Blake Goodman
- Department of Gynecologic Oncology, U.T.M.D. Anderson Cancer Center, 1155 Herman Pressler Boulevard, Unit 1362, Houston, TX 77030
| | - Hee-Dong Han
- Department of Gynecologic Oncology, U.T.M.D. Anderson Cancer Center, 1155 Herman Pressler Boulevard, Unit 1362, Houston, TX 77030
- Center for RNA Interference and Non-Coding RNA, U.T.M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030
| | - Alpa M. Nick
- Department of Gynecologic Oncology, U.T.M.D. Anderson Cancer Center, 1155 Herman Pressler Boulevard, Unit 1362, Houston, TX 77030
| | - Rebecca L. Stone
- Department of Gynecologic Oncology, U.T.M.D. Anderson Cancer Center, 1155 Herman Pressler Boulevard, Unit 1362, Houston, TX 77030
| | - Robert L. Coleman
- Department of Gynecologic Oncology, U.T.M.D. Anderson Cancer Center, 1155 Herman Pressler Boulevard, Unit 1362, Houston, TX 77030
| | - Ronald D. Alvarez
- Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Gabriel Lopez-Berestein
- Department of Experimental Therapeutics, U.T.M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 422, Houston, TX 77030
- Center for RNA Interference and Non-Coding RNA, U.T.M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030
| | - Anil K. Sood
- Department of Gynecologic Oncology, U.T.M.D. Anderson Cancer Center, 1155 Herman Pressler Boulevard, Unit 1362, Houston, TX 77030
- Department of Cancer Biology, U.T.M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 173, Houston, TX 77030
- Center for RNA Interference and Non-Coding RNA, U.T.M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030
| | - Charles N. Landen
- Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL 35294
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Abstract
We describe a unique case of a bilateral osteochondrosis of the femoral heads, similar to Perthes disease, in a boy affected by Alagille syndrome. This is a rare genetic syndrome, caused by vascular anomalies, and characterized by five main features: hepatic, cardiovascular, ophthalmological, skeletal malformations, and characteristic facial appearance. The most frequent skeletal finding is the 'butterfly vertebra'. We have followed the patient from the age of 5 years to the age of 20 years. We performed two bilateral valgus osteotomies when he was 10 years old to limit the progression of the deformity. We believe that the association of a bilateral osteochondrosis of the femoral heads with Alagille syndrome, a disease characterized by a vascular etiology, supports the hypothesis of angiogenic pathogenesis of Perthes disease.
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Abstract
In most cholangiopathies, liver diseases of different etiologies in which the biliary epithelium is the primary target in the pathogenic sequence, the central mechanism involves inflammation. Inflammation, characterized by pleomorphic peribiliary infiltrate containing fibroblasts, macrophages, lymphocytes, as well as endothelial cells and pericytes, is associated to the emergence of "reactive cholangiocytes." These biliary cells do not possess bile secretory functions, are in contiguity with terminal cholangioles, and are of a less-differentiated phenotype. They have acquired several mesenchymal properties, including motility and ability to secrete a vast number of proinflammatory chemo/cytokines and growth factors along with de novo expression of a rich receptor machinery. These functional properties enable reactive cholangiocytes to establish intimate contacts and to mutually exchange a variety of paracrine signals with the different mesenchymal cell types populating the portal infiltrate. The extensive crosstalk between the epithelial and mesenchymal compartments is the driver of liver repair mechanisms in cholangiopathies, ultimately evolving toward portal fibrosis. Herein, the authors first review the properties of the different cell types involved in their interaction, and then analyze the underlying molecular mechanisms as they relate to liver repair in cholangiopathies.
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Affiliation(s)
- Luca Fabris
- Department of Surgical and Gastroenterological Sciences, University of Padua, Padova, Italy
- Center for Liver Research (CeLiveR), Bergamo, Italy
| | - Mario Strazzabosco
- Center for Liver Research (CeLiveR), Bergamo, Italy
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut
- Department of Clinical Medicine, University of Milano-Bicocca, Milan, Italy
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Abstract
OBJECTIVE The aim of the study was to study the clinical and histological features of Alagille syndrome (AGS) at presentation comparing the value of the various modalities before the implementation of genetic diagnosis. PATIENTS AND METHODS We performed a retrospective analysis of the records of 117 children diagnosed as having AGS after referral to King's College Hospital between 1980 and 2005. RESULTS Cholestasis was seen in 104 of 117 (89%), characteristic facies in 91 of 117 (77%), posterior embryotoxon in 72 of 117 (61%), butterfly vertebrae in 44 of 117 (39%), heart disease (most often peripheral pulmonary stenosis) in 107 of 117 (91%), and renal disease in 27 of 117 (23%). Serum cholesterol levels of >5 mmol/L were seen in 52 of 86 (60.4%). Liver biopsy showed characteristic features of paucity of interlobular bile ducts in 59 of 77 (76.6%) children younger than 16 weeks of age, in 10 of 14 (71.4%) between 16 weeks and 1 year of age, and in 8 of 12 (66.66%) older than 1 year of age. Other biopsy findings were those of nonspecific hepatitis and biliary features. Iminodiacetic acid scans showed no excretion of isotope into the bowel after 24 hours in 21 of 35 (60%), and small/no gallbladder on ultrasound was seen in 29 of 104 (27.8%). Eleven of 117 (9.4%) had a diagnostic laparotomy and operative cholangiography, 2 proceeding to Kasai portoenterostomy before referral to our unit. CONCLUSIONS Clinical features of AGS are not as consistently informative as suggested in the literature. Hypercholesterolaemia is nonspecific but may be a helpful pointer. Histology is not characteristic in 25%; hepatobiliary iminodiacetic acid scan and ultrasound may suggest a false diagnosis of biliary atresia in 60% and 28%, respectively, supporting the concept that infants with liver disease warrant early referral to a specialist centre. The advent of genetic diagnosis will redefine the syndrome with likely effects on the prognosis of the defined group.
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Hofmann JJ, Zovein AC, Koh H, Radtke F, Weinmaster G, Iruela-Arispe ML. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 2010; 137:4061-72. [PMID: 21062863 DOI: 10.1242/dev.052118] [Citation(s) in RCA: 184] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Mutations in the human Notch ligand jagged 1 (JAG1) result in a multi-system disorder called Alagille syndrome (AGS). AGS is chiefly characterized by a paucity of intrahepatic bile ducts (IHBD), but also includes cardiac, ocular, skeletal, craniofacial and renal defects. The disease penetration and severity of the affected organs can vary significantly and the molecular basis for this broad spectrum of pathology is unclear. Here, we report that Jag1 inactivation in the portal vein mesenchyme (PVM), but not in the endothelium of mice, leads to the hepatic defects associated with AGS. Loss of Jag1 expression in SM22α-positive cells of the PVM leads to defective bile duct development beyond the initial formation of the ductal plate. Cytokeratin 19-positive cells are detected surrounding the portal vein, yet they are unable to form biliary tubes, revealing an instructive role of the vasculature in liver development. These findings uncover the cellular basis for the defining feature of AGS, identify mesenchymal Jag1-dependent and -independent stages of duct development, and provide mechanistic information for the role of Jag1 in IHBD formation.
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Affiliation(s)
- Jennifer J Hofmann
- Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA 90095, USA
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Elisofon SA, Emerick KM, Sinacore JM, Alonso EM. Health status of patients with Alagille syndrome. J Pediatr Gastroenterol Nutr 2010; 51:759-65. [PMID: 20948445 DOI: 10.1097/mpg.0b013e3181ef3771] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES The aim of the study was to assess health-related quality of life (HRQOL) in children with Alagille syndrome (AGS) in comparison with a normative population and other chronic diseases, and also to examine the effect of AGS-specific morbidities on HRQOL. PATIENTS AND METHODS A cross-sectional study was performed using the Child Health Questionnaire Parent Form 50 (CHQ-PF50) to measure HRQOL in patients with AGS. AGS HRQOL was compared with that of a normative population and those previously studied by the CHQ, including juvenile rheumatoid arthritis, attention-deficit/hyperactivity disorder, and liver transplantation. AGS-specific questions were used in multiple regression analysis to determine correlation of features and symptoms of AGS with HRQOL. RESULTS Seventy-one patients with AGS, ages 5 to 18 years, were studied. Those families completing surveys demonstrated that children with AGS had significantly lower HRQOL (P < 0.05) compared with the normative sample. In comparison with children with juvenile rheumatoid arthritis, children with AGS had lower psychosocial function scores (P < 0.0005). In comparison with children with attention-deficit/hyperactivity disorder, children with AGS had lower physical function scores (P < 0.0005) but higher psychosocial function scores (P < 0.0005). Children with AGS had lower physical function scores than a liver transplant population (P < 0.05). Regression analysis indicated that cardiac catheterization or surgery, mental health diagnoses, and poor sleep were associated with lower CHQ scores in children with AGS. CONCLUSIONS In the first descriptive report of HRQOL in a large cohort of patients with AGS, HRQOL was impaired, indicating a significant burden of chronic disease in both physical and psychosocial health. Additional prospective evaluation is needed in multicenter collaboration.
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Affiliation(s)
- Scott A Elisofon
- Division of Pediatric Gastroenterology and Nutrition, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
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44
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Oldershaw RA, Hardingham TE. Notch signaling during chondrogenesis of human bone marrow stem cells. Bone 2010; 46:286-93. [PMID: 19406255 DOI: 10.1016/j.bone.2009.04.242] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2009] [Revised: 04/14/2009] [Accepted: 04/15/2009] [Indexed: 01/15/2023]
Abstract
Notch signaling is an important mechanism involved in early development which helps to determine the differentiation and fate of cells destined to form different tissues in the body. Its role in the differentiation of adult stem cells, such as those found in bone marrow is much less clear. As there is great interest in the potential of human bone marrow stem cells (hMSC) as a source of cells for the repair of articular cartilage and other tissues, it is important to understand if Notch signaling promotes or suppresses differentiation. Using primary human bone marrow stem cells (hMSC) in 3D cell aggregate culture a new study has investigated the expression of the canonical Notch pathway genes during chondrogenesis and showed that the Notch ligand, Jagged1 (JAG1) sharply increased in expression peaking early in differentiation. A Notch target gene, HEY1, was also expressed with a temporal profile, which closely followed the expression of JAG1 and this preceded the rise in type II collagen expression that characterized chondrogenesis. The JAG1 mediated Notch signaling was shown with a Notch inhibitor (DAPT) to be necessary for chondrogenesis, as inhibition days 0-14, or just days 0-5, blocked chondrogenesis, whereas Notch inhibition days 5-14 did not. In further experiments Notch signaling was shown to be critical for full chondrogenesis, as adenoviral hJAG1 transduction of hMSCs, which caused continuous expression of JAG1 and sustained Notch signaling, completely blocked chondrogenesis. In these cultures there was inhibited production of extracellular matrix and failure to differentiate was interpreted as the retention of the hMSC in a pre-chondrogenic state. The results in this study thus showed that JAG1 mediated Notch signaling in hMSC was necessary to initiate chondrogenesis, but must be switched off for chondrogenesis to proceed and it will be important to establish if this is a mechanism common to all chondrocyte differentiation.
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Affiliation(s)
- Rachel A Oldershaw
- North West Embryonic Stem Cell Centre, Faculty of Life Sciences, University of Manchester, Manchester, M13 9NT UK
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45
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Shrivastava R, Williams A, Mikhail A, Roberts D, Richards M, Aithal V. An unusual cause of hypertension and renal failure: a case series of a family with Alagille syndrome. Nephrol Dial Transplant 2009; 25:1501-6. [PMID: 20042397 DOI: 10.1093/ndt/gfp692] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Alagille Syndrome (OMIM 118450) is a multisystem developmental disorder inherited in an autosomal dominant pattern with variable expression. It commonly manifests in children with early cholestatic jaundice due to paucity of interlobular biliary ducts. Renal involvement is less common but can take various forms including renovascular disease, renal agenesis or hypoplasia, cystic renal disease, mesangiolipidosis, tubulointerstitial nephritis and renal tubular acidosis. We describe a family of Alagille syndrome with JAG 1 mutation running through at least two generations, affecting four members with variable phenotypic expressions and disease severity. Alagille syndrome should be considered in the differential diagnosis of adults with renovascular disease and children with agenesis/dysgenesis of kidney and reflux nephropathy even in the absence of hepatic disease. Renal transplant can be successful in these patients although living related donation may not be appropriate given the high penetrance and variable expression of this condition. This syndrome may cause symptomatic bradyarrhythmias as described in our series.
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46
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Dyack S, Cameron M, Otley A, Greer W. An autosomal recessive form of Alagille-like syndrome that is not linked to JAG1. Genet Med 2009; 9:544-50. [PMID: 17700393 DOI: 10.1097/gim.0b013e318133a802] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
PURPOSE Alagille syndrome is an autosomal dominant condition characterized by a paucity of interlobular bile ducts and chronic cholestasis, cardiac disease, skeletal abnormalities, ocular abnormalities, and characteristic facies. Most cases harbor a mutation in JAG1. We describe a large consanguineous family with five individuals affected with an Alagille-like syndrome that appears to be autosomal recessive. Our objective was to characterize the disorder clinically and determine whether affected individuals had inherited a mutation in JAG1. METHODS Clinical data were obtained through questioning and patient chart review. Linkage analysis using microsatellite markers was used to assess the possibility of a JAG1 mutation. RESULTS The clinical phenotype of patients was not entirely consistent with classic Alagille syndrome. All affected individuals had neonatal cholestasis with intrahepatic bile duct paucity, with three having pulmonary stenosis, but the presentation was unusually uniform and severe in childhood. There was no evidence of posterior embryotoxon or vertebral anomalies. Cardiac abnormalities were inconsistent between patients. Most significantly, the pedigree suggested an autosomal recessive form of inheritance. Linkage analysis excluded a mutation in JAG1. CONCLUSIONS We have identified a kindred with an Alagille-like syndrome with an autosomal recessive form of inheritance not caused by a mutation in JAG1.
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Affiliation(s)
- Sarah Dyack
- Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada
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Zong Y, Panikkar A, Xu J, Antoniou A, Raynaud P, Lemaigre F, Stanger BZ. Notch signaling controls liver development by regulating biliary differentiation. Development 2009; 136:1727-39. [PMID: 19369401 DOI: 10.1242/dev.029140] [Citation(s) in RCA: 346] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
In the mammalian liver, bile is transported to the intestine through an intricate network of bile ducts. Notch signaling is required for normal duct formation, but its mode of action has been unclear. Here, we show in mice that bile ducts arise through a novel mechanism of tubulogenesis involving sequential radial differentiation. Notch signaling is activated in a subset of liver progenitor cells fated to become ductal cells, and pathway activation is necessary for biliary fate. Notch signals are also required for bile duct morphogenesis, and activation of Notch signaling in the hepatic lobule promotes ectopic biliary differentiation and tubule formation in a dose-dependent manner. Remarkably, activation of Notch signaling in postnatal hepatocytes causes them to adopt a biliary fate through a process of reprogramming that recapitulates normal bile duct development. These results reconcile previous conflicting reports about the role of Notch during liver development and suggest that Notch acts by coordinating biliary differentiation and morphogenesis.
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Affiliation(s)
- Yiwei Zong
- Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
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Abstract
Hardikar syndrome (HS) is a disorder of multiple anomalies predominantly characterized by cleft lip/palate, liver and biliary tract disease, intestinal malrotation, obstructive uropathy, and retinopathy. To date, three patients have been reported with the unusual constellation of chronic liver/biliary tract disease and obvious defects in organogenesis [Hardikar et al. (1992): Am J Med Genet 44: 13-17; Cools and Jaeken (1997): Am J Med Genet 71: 472-474]. With this report, we add another patient with this syndrome. New features, hitherto not reported, were vaginal atresia, a type 1 choledochal cyst and, owing to the progressive nature of the liver disease, the need for liver transplantation. It is intriguing to speculate, that HS could be genetically related to Alagille syndrome (AS), since both conditions share an unusual number of phenotypic abnormalities.
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Affiliation(s)
- J Rainer Poley
- Department of Pediatrics, Section of Pediatric Gastroenterology and Hepatology, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27834, USA.
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Roskams T, Desmet V. Embryology of extra- and intrahepatic bile ducts, the ductal plate. Anat Rec (Hoboken) 2008; 291:628-35. [PMID: 18484608 DOI: 10.1002/ar.20710] [Citation(s) in RCA: 129] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In the human embryo, the first anlage of the bile ducts and the liver is the hepatic diverticulum or liver bud. For up to 8 weeks of gestation, the extrahepatic biliary tree develops through lengthening of the caudal part of the hepatic diverticulum. This structure is patent from the beginning and remains patent and in continuity with the developing liver at all stages. The hepatic duct (ductus hepaticus) develops from the cranial part (pars hepatica) of the hepatic diverticulum. The distal portions of the right and left hepatic ducts develop from the extrahepatic ducts and are clearly defined tubular structures by 12 weeks of gestation. The proximal portions of the main hilar ducts derive from the first intrahepatic ductal plates. The extrahepatic bile ducts and the developing intrahepatic biliary tree maintain luminal continuity from the very start of organogenesis throughout further development, contradicting a previous study in the mouse suggesting that the extrahepatic bile duct system develops independently from the intrahepatic biliary tree and that the systems are initially discontinuous but join up later. The normal development of intrahepatic bile ducts requires finely timed and precisely tuned epithelial-mesenchymal interactions, which proceed from the hilum of the liver toward its periphery along the branches of the developing portal vein. Lack of remodeling of the ductal plate results in the persistence of an excess of embryonic bile duct structures remaining in their primitive ductal plate configuration. This abnormality has been termed the ductal plate malformation.
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Affiliation(s)
- T Roskams
- Department of Morphology and Molecular Pathology, University of Leuven, Leuven, Belgium.
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50
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Oldershaw RA, Tew SR, Russell AM, Meade K, Hawkins R, McKay TR, Brennan KR, Hardingham TE. Notch signaling through Jagged-1 is necessary to initiate chondrogenesis in human bone marrow stromal cells but must be switched off to complete chondrogenesis. Stem Cells 2008; 26:666-74. [PMID: 18192230 DOI: 10.1634/stemcells.2007-0806] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We investigated Notch signaling during chondrogenesis in human bone marrow stromal cells (hMSC) in three-dimensional cell aggregate culture. Expression analysis of Notch pathway genes in 14-day chondrogenic cultures showed that the Notch ligand Jagged-1 (Jag-1) sharply increased in expression, peaking at day 2, and then declined. A Notch target gene, HEY-1, was also expressed, with a temporal profile that closely followed the expression of Jag-1, and this preceded the rise in type II collagen expression that characterized chondrogenesis. We demonstrated that the shut-down in Notch signaling was critical for full chondrogenesis, as adenoviral human Jag-1 transduction of hMSC, which caused continuous elevated expression of Jag-1 and sustained Notch signaling over 14 days, completely blocked chondrogenesis. In these cultures, there was inhibited production of extracellular matrix, and the gene expression of aggrecan and type II collagen were strongly suppressed; this may reflect the retention of a prechondrogenic state. The JAG-1-mediated Notch signaling was also shown to be necessary for chondrogenesis, as N-[N-(3,5-difluorophenacetyl-L-alanyl)]-(S)-phenylglycine t-butyl ester (DAPT) added to cultures on days 0-14 or just days 0-5 inhibited chondrogenesis, but DAPT added from day 5 did not. The results thus showed that Jag-1-mediated Notch signaling in hMSC was necessary to initiate chondrogenesis, but it must be switched off for chondrogenesis to proceed.
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Affiliation(s)
- Rachel A Oldershaw
- UK Centre for Tissue Engineering, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom
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