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1
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Nadar-Ponniah PT, Lopez-Escamez JA. Preclinical Models to Study the Molecular Pathophysiology of Meniere's Disease: A Pathway to Gene Therapy. J Clin Med 2025; 14:1427. [PMID: 40094841 PMCID: PMC11899769 DOI: 10.3390/jcm14051427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/11/2025] [Accepted: 02/17/2025] [Indexed: 03/19/2025] Open
Abstract
Background: Meniere's disease (MD) is a set of rare disorders that affects >4 million people worldwide. Individuals with MD suffer from episodes of vertigo associated with fluctuating sensorineural hearing loss and tinnitus. Hearing loss can involve one or both ears. Over 10% of the reported cases are observed in families, suggesting its significant genetic contribution. The condition is polygenic with >20 genes, and several patterns of inheritance have been reported, including autosomal dominant, autosomal recessive, and digenic inheritance across multiple MD families. Preclinical research using animal models has been an indispensable tool for studying the neurophysiology of the auditory and vestibular systems and to get a better understanding of the functional role of genes that are involved in the hearing and vestibular dysfunction. While mouse models are the most used preclinical model, this review analyzes alternative animal and non-animal models that can be used to study MD genes. Methods: A literature search of the 21 genes reported for familial MD and the preclinical models used to investigate their functional role was performed. Results: Comparing the homology of proteins encoded by these genes to other model organisms revealed Drosophila and zebrafish as cost-effective models to screen multiple genes and study the pathophysiology of MD. Conclusions: Murine models are preferred for a quantitative neurophysiological assessment of hearing and vestibular functions to develop drug or gene therapy.
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Affiliation(s)
- Prathamesh T. Nadar-Ponniah
- Meniere Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, University of Sydney, Sydney, NSW 2065, Australia
| | - Jose A. Lopez-Escamez
- Meniere Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, University of Sydney, Sydney, NSW 2065, Australia
- Otology & Neurotology Group CTS495, Division of Otolaryngology, Department of Surgery, Instituto de Investigación Biosanitaria, ibs.GRANADA, Universidad de Granada, 18071 Granada, Spain
- Sensorineural Pathology Programme, Centro de Investigación Biomédica en Red en Enfermedades Raras, CIBERER, 28029 Madrid, Spain
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2
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Tsukada K, Nishio SY, Takumi Y, Usami SI. Comparison of vestibular function in hereditary hearing loss patients with GJB2, CDH23, and SLC26A4 variants. Sci Rep 2024; 14:10596. [PMID: 38720048 PMCID: PMC11078969 DOI: 10.1038/s41598-024-61442-3] [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: 12/23/2023] [Accepted: 05/06/2024] [Indexed: 05/12/2024] Open
Abstract
To investigate the association between hereditary hearing loss and vestibular function, we compared vestibular function and symptoms among patients with GJB2, SLC26A4, and CDH23 variants. Thirty-nine patients with sensory neural hearing loss (11 males and 28 females) with biallelic pathogenic variants in either GJB2, SLC26A4, or CDH23 were included in this study (13 GJB2, 15 SLC26A4, and 11 CDH23). The patients were examined using caloric testing and cervical and ocular vestibular-evoked myogenic potentials (cVEMP and oVEMP). We also compared vestibular function and symptoms between patients with these gene variants and 78 normal-hearing ears without vestibular symptoms as controls. The frequency of semicircular canal hypofunction in caloric testing was higher in patients with SLC26A4 variants (47%) than in those with GJB2 (0%) and CDH23 variants (27%). According to the cVEMP results, 69% of patients with GJB2 variants had saccular hypofunction, a significantly higher proportion than in those carrying other variants (SLC26A4, 20%; CDH23, 18%). In oVEMP, which reflects utricular function, no difference was observed in the frequency of hypofunction among the three genes (GJB2, 15%; SLC26A4, 40%; and CDH23, 36%). Hence, discernable trends indicate vestibular dysfunction associated with each gene.
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Affiliation(s)
- Keita Tsukada
- Department of Otorhinolaryngology Head and Neck Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
| | - Shin-Ya Nishio
- Department of Hearing Implant Sciences, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan
| | - Yutaka Takumi
- Department of Otorhinolaryngology Head and Neck Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan
| | - Shin-Ichi Usami
- Department of Hearing Implant Sciences, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan
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3
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Yu SL, Jeong DU, Noh EJ, Jeon HJ, Lee DC, Kang M, Kim TH, Lee SK, Han AR, Kang J, Park SR. Exosomal miR-205-5p Improves Endometrial Receptivity by Upregulating E-Cadherin Expression through ZEB1 Inhibition. Int J Mol Sci 2023; 24:15149. [PMID: 37894829 PMCID: PMC10607375 DOI: 10.3390/ijms242015149] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/07/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
Endometrial receptivity is a complex process that prepares the uterine endometrium for embryo implantation; insufficient endometrial receptivity is one of the causes of implantation failure. Here, we analyzed the microRNA expression profiles of exosomes derived from both receptive (RL95-2) and non-receptive (AN3-CA) endometrial epithelial cell (EEC) lines to identify exosomal miRNAs closely linked to endometrial receptivity. Among the 466 differentially expressed miRNAs, miR-205-5p was the most highly expressed in exosomes secreted from receptive RL95-2 cells. miR-205-5p, enriched at the adhesive junction, was closely related to endometrial receptivity. ZEB1, a transcriptional repressor of E-cadherin associated with endometrial receptivity, was identified as a direct target of miR-205-5p. miR-205-5p expression was significantly lower in the endometrial tissues of infertile women than in that of non-infertile women. In vivo, miR-205-5p expression was upregulated in the post-ovulatory phase, and its inhibitor reduced embryo implantation. Furthermore, administration of genetically modified exosomes overexpressing miR-205-5p mimics upregulated E-cadherin expression by targeting ZEB1 and improved spheroid attachment of non-receptive AN3-CA cells. These results suggest that the miR-205-5p/ZEB1/E-cadherin axis plays an important role in regulating endometrial receptivity. Thus, the use of exosomes harboring miR-205-5p mimics can be considered a potential therapeutic approach for improving embryo implantation.
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Affiliation(s)
- Seong-Lan Yu
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea; (S.-L.Y.); (D.-U.J.); (H.J.J.); (T.-H.K.); (S.K.L.)
| | - Da-Un Jeong
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea; (S.-L.Y.); (D.-U.J.); (H.J.J.); (T.-H.K.); (S.K.L.)
| | - Eui-Jeong Noh
- Department of Obstetrics and Gynecology, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea;
| | - Hye Jin Jeon
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea; (S.-L.Y.); (D.-U.J.); (H.J.J.); (T.-H.K.); (S.K.L.)
| | - Dong Chul Lee
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea; (D.C.L.); (M.K.)
- Department of Functional Genomics, KRIBB School of Bioscience, University of Science and Technology, Daejeon 34141, Republic of Korea
| | - Minho Kang
- Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea; (D.C.L.); (M.K.)
| | - Tae-Hyun Kim
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea; (S.-L.Y.); (D.-U.J.); (H.J.J.); (T.-H.K.); (S.K.L.)
- Department of Obstetrics and Gynecology, Konyang University Hospital, Daejeon 35365, Republic of Korea
| | - Sung Ki Lee
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea; (S.-L.Y.); (D.-U.J.); (H.J.J.); (T.-H.K.); (S.K.L.)
- Department of Obstetrics and Gynecology, Konyang University Hospital, Daejeon 35365, Republic of Korea
| | - Ae Ra Han
- I-Dream Clinic, Department of Obstetrics and Gynecology, Mizmedi Hospital, Seoul 07639, Republic of Korea;
- Daegu CHA Fertility Center, CHA University, Daegu 42469, Republic of Korea
| | - Jaeku Kang
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea; (S.-L.Y.); (D.-U.J.); (H.J.J.); (T.-H.K.); (S.K.L.)
- Department of Pharmacology, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea
| | - Seok-Rae Park
- Priority Research Center, Myunggok Medical Research Institute, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea; (S.-L.Y.); (D.-U.J.); (H.J.J.); (T.-H.K.); (S.K.L.)
- Department of Microbiology, College of Medicine, Konyang University, Daejeon 35365, Republic of Korea
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4
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Liman N, Sağsöz H. The immunolocalization of cadherins and beta-catenin in the cervix and vagina of cycling cows. Vet Res Commun 2023; 47:1155-1175. [PMID: 36729278 DOI: 10.1007/s11259-023-10075-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 01/14/2023] [Indexed: 02/03/2023]
Abstract
The adherens junctions (AJs) maintain the epithelial cell layers' structural integrity and barrier function. AJs also play a vital role in various biological and pathological processes. AJs perform these functions through the cadherin-catenin adhesion complex. This study investigated the presence, cell-specific localization, and temporal distribution of AJ components such as classical type I cadherins and beta-catenin in the cow cervix and vagina during the estrous cycle. Immunohistochemistry and Western blot analysis results demonstrated that beta-catenin and epithelial (E)-, neural (N)-, and placental (P)-cadherins are expressed in the cow cervix and vagina during the estrous cycle. These adhesion molecules were localized in the membrane and cytoplasm of the ciliated and non-ciliated cervical cells and the stratified vaginal epithelial cells. Positive immunostaining for P-, N-cadherin, and beta-catenin was also observed in the vascular endothelial cells of the cervical and vaginal stroma. Quantitative immunohistochemistry examinations revealed that in the cervical and vaginal epithelia, P-cadherin's optical density values (ODv) were the highest; in contrast, the N-cadherin ODv were the lowest. The ODv of P-cadherin and beta-catenin in the cervical epithelium and E-cadherin in the vagina were significantly higher in the luteal phase versus the follicular phase of the estrous cycle. Furthermore, the ODv of P-cadherin, N-cadherin, and beta-catenin in the cervix's central and peripheral epithelial regions were different during the estrous cycle. These findings indicate that classical cadherins and beta-catenin in the cervix and vagina exhibit cell- and tissue-specific expression patterns under the influence of estrogen and progesterone hormones during the estrous cycle.
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Affiliation(s)
- Narin Liman
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Erciyes University, 38039, Kayseri, Turkey.
| | - Hakan Sağsöz
- Department of Histology and Embryology, Faculty of Veterinary Medicine, Dicle University, Diyarbakır, Turkey
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5
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Chen XM, Xue XM, Yu N, Guo WW, Yuan SL, Jiang QQ, Yang SM. The Role of Genetic Variants in the Susceptibility of Noise-Induced Hearing Loss. Front Cell Neurosci 2022; 16:946206. [PMID: 35903368 PMCID: PMC9315435 DOI: 10.3389/fncel.2022.946206] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 06/17/2022] [Indexed: 11/24/2022] Open
Abstract
Noised-induced hearing loss (NIHL) is an acquired, progressive neurological damage caused by exposure to intense noise in various environments including industrial, military and entertaining settings. The prevalence of NIHL is much higher than other occupational injuries in industrialized countries. Recent studies have revealed that genetic factors, together with environmental conditions, also contribute to NIHL. A group of genes which are linked to the susceptibility of NIHL had been uncovered, involving the progression of oxidative stress, potassium ion cycling, cilia structure, heat shock protein 70 (HSP70), DNA damage repair, apoptosis, and some other genes. In this review, we briefly summarized the studies primary in population and some animal researches concerning the susceptible genes of NIHL, intending to give insights into the further exploration of NIHL prevention and individual treatment.
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Affiliation(s)
- Xue-min Chen
- Medical School of Chinese PLA, Beijing, China
- Senior Department of Otolaryngology-Head & Neck Surgery, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, China
- State Key Lab of Hearing Science, Ministry of Education, Beijing, China
- Beijing Key Lab of Hearing Impairment Prevention and Treatment, Beijing, China
| | - Xin-miao Xue
- Medical School of Chinese PLA, Beijing, China
- Senior Department of Otolaryngology-Head & Neck Surgery, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, China
- State Key Lab of Hearing Science, Ministry of Education, Beijing, China
- Beijing Key Lab of Hearing Impairment Prevention and Treatment, Beijing, China
| | - Ning Yu
- Senior Department of Otolaryngology-Head & Neck Surgery, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, China
- State Key Lab of Hearing Science, Ministry of Education, Beijing, China
- Beijing Key Lab of Hearing Impairment Prevention and Treatment, Beijing, China
| | - Wei-wei Guo
- Senior Department of Otolaryngology-Head & Neck Surgery, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, China
- State Key Lab of Hearing Science, Ministry of Education, Beijing, China
- Beijing Key Lab of Hearing Impairment Prevention and Treatment, Beijing, China
| | - Shuo-long Yuan
- Senior Department of Otolaryngology-Head & Neck Surgery, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, China
- State Key Lab of Hearing Science, Ministry of Education, Beijing, China
- Beijing Key Lab of Hearing Impairment Prevention and Treatment, Beijing, China
| | - Qing-qing Jiang
- Senior Department of Otolaryngology-Head & Neck Surgery, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, China
- State Key Lab of Hearing Science, Ministry of Education, Beijing, China
- Beijing Key Lab of Hearing Impairment Prevention and Treatment, Beijing, China
| | - Shi-ming Yang
- Senior Department of Otolaryngology-Head & Neck Surgery, Chinese PLA General Hospital, Beijing, China
- National Clinical Research Center for Otolaryngologic Diseases, Beijing, China
- State Key Lab of Hearing Science, Ministry of Education, Beijing, China
- Beijing Key Lab of Hearing Impairment Prevention and Treatment, Beijing, China
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6
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Recknagel H, Carruthers M, Yurchenko AA, Nokhbatolfoghahai M, Kamenos NA, Bain MM, Elmer KR. The functional genetic architecture of egg-laying and live-bearing reproduction in common lizards. Nat Ecol Evol 2021; 5:1546-1556. [PMID: 34621056 DOI: 10.1038/s41559-021-01555-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 08/20/2021] [Indexed: 02/07/2023]
Abstract
All amniotes reproduce either by egg-laying (oviparity), which is ancestral to vertebrates or by live-bearing (viviparity), which has evolved many times independently. However, the genetic basis of these parity modes has never been resolved and, consequently, its convergence across evolutionary scales is currently unknown. Here, we leveraged natural hybridizations between oviparous and viviparous common lizards (Zootoca vivipara) to describe the functional genes and genetic architecture of parity mode and its key traits, eggshell and gestation length, and compared our findings across vertebrates. In these lizards, parity trait genes were associated with progesterone-binding functions and enriched for tissue remodelling and immune system pathways. Viviparity involved more genes and complex gene networks than did oviparity. Angiogenesis, vascular endothelial growth and adrenoreceptor pathways were enriched in the viviparous female reproductive tissue, while pathways for transforming growth factor were enriched in the oviparous. Natural selection on these parity mode genes was evident genome-wide. Our comparison to seven independent origins of viviparity in mammals, squamates and fish showed that genes active in pregnancy were related to immunity, tissue remodelling and blood vessel generation. Therefore, our results suggest that pre-established regulatory networks are repeatedly recruited for viviparity and that these are shared at deep evolutionary scales.
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Affiliation(s)
- Hans Recknagel
- Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK.,Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Madeleine Carruthers
- Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK.,School of Biological Sciences, University of Bristol, Bristol, UK
| | - Andrey A Yurchenko
- Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK.,Inserm U981, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France
| | - Mohsen Nokhbatolfoghahai
- Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK
| | - Nicholas A Kamenos
- School of Geographical and Earth Sciences, University of Glasgow, Glasgow, UK
| | - Maureen M Bain
- Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK
| | - Kathryn R Elmer
- Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK.
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7
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Nazarian H, Novin MG, Khaleghi S, Habibi B. Small non-coding RNAs in embryonic pre-implantation. Curr Mol Med 2021; 22:287-299. [PMID: 34042034 DOI: 10.2174/1566524021666210526162917] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 04/02/2021] [Accepted: 04/03/2021] [Indexed: 11/22/2022]
Abstract
Failure of embryo implantation has been introduced as an important limiting parameter in early assisted reproduction and pregnancy. The embryo-maternal interactions, endometrial receptivity, and detections of implantation consist of the embryo viability. For regulating the implantation, multiple molecules may be consisted, however, their specific regulatory mechanisms still stand unclear. MicroRNAs (miRNAs) have been highly concerned due to their important effect on human embryo implantation. MicroRNA (miRNA), which acts as the transcriptional regulator of gene expression, is consisted in embryo implantation. Scholars determined that miRNAs cannot affect the cells and release by cells in the extracellular environment considering facilitating intercellular communication, multiple packaging forms, and preparing indicative data in the case of pathological and physiological conditions. The detection of extracellular miRNAs provided new information in cases of implantation studies. For embryo-maternal communication, MiRNAs offered novel approaches. In addition, in assisted reproduction, for embryo choice and prediction of endometrial receptivity, they can act as non-invasive biomarkers and can enhance the accuracy in the process of reducing the mechanical damage for the tissue.
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Affiliation(s)
- Hamid Nazarian
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marefat Ghaffari Novin
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Khaleghi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bahare Habibi
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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8
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Mohammadzadeh M, Pourentezari M, Zare-Zardini H, Nabi A, Esmailabad SG, Khodadadian A, Talebi AR. The effects of sesame oil and different doses of estradiol on testicular structure, sperm parameters, and chromatin integrity in old mice. Clin Exp Reprod Med 2021; 48:34-42. [PMID: 33648043 PMCID: PMC7943348 DOI: 10.5653/cerm.2020.03524] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 04/25/2020] [Indexed: 01/04/2023] Open
Abstract
Objective Studies of the effects of estrogens on the male reproductive system have emphasized the role of these hormones in male fertility. Sesame oil has many phytoestrogenic compounds and may improve male fertility. This study investigated the effects of sesame oil and different concentrations of estrogen on sperm parameters and DNA integrity in male mice. Methods Twenty old NMRI (The Naval Medical Research Institute) male mice (40 weeks; weight, 30–35 g) were treated with sesame oil or different concentrations of estrogen (estradiol, 1 and 10 μL/kg/day) or received no treatment (controls). After 35 days, sperm parameters and DNA integrity were assessed and analyzed. Results Sperm count, progressive motility, and morphology were decreased in the group that received 10 μL/kg of estradiol. A remarkably lower percentage of DNA fragmentation and protamine deficiency were detected in the group that received 1 μL/kg of estradiol. In the groups that received sesame oil and 1 μL/kg of estradiol, the numbers of spermatogonia and Leydig cells were higher than in controls. The combination of sesame oil and 1 μL/kg of estradiol led to improved sperm parameters and chromatin and testicular structure. Conclusion Based on this study, consumption of sesame oil and a low concentration of estradiol may improve testicular function in older mice.
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Affiliation(s)
- Masoomeh Mohammadzadeh
- Department of Reproductive Biology, Yazd Reproductive Sciences Institute, Research and Clinical Center for Infertility, Yazd, Iran
| | - Majid Pourentezari
- Department of Biology and Anatomical Sciences, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hadi Zare-Zardini
- Department of Hematology and Oncology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Department of Sciences, Farhangian University, Isfahan, Iran.,Medical Nanotechnology and Tissue Engineering Research Center, Yazd Reproductive Sciences Institute, Yazd, Iran
| | - Ali Nabi
- Department of Reproductive Biology, Yazd Reproductive Sciences Institute, Research and Clinical Center for Infertility, Yazd, Iran
| | - Saeed Ghasemi Esmailabad
- Department of Reproductive Biology, Yazd Reproductive Sciences Institute, Research and Clinical Center for Infertility, Yazd, Iran
| | - Ali Khodadadian
- Department of Medical Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ali Reza Talebi
- Department of Reproductive Biology, Yazd Reproductive Sciences Institute, Research and Clinical Center for Infertility, Yazd, Iran
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9
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Identification of Novel CDH23 Variants Causing Moderate to Profound Progressive Nonsyndromic Hearing Loss. Genes (Basel) 2020; 11:genes11121474. [PMID: 33316915 PMCID: PMC7764456 DOI: 10.3390/genes11121474] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 01/12/2023] Open
Abstract
Mutant alleles of CDH23, a gene that encodes a putative calcium-dependent cell-adhesion glycoprotein with multiple cadherin-like domains, are responsible for both recessive DFNB12 nonsyndromic hearing loss (NSHL) and Usher syndrome 1D (USH1D). The encoded protein cadherin 23 (CDH23) plays a vital role in maintaining normal cochlear and retinal function. The present study’s objective was to elucidate the role of DFNB12 allelic variants of CDH23 in Saudi Arabian patients. Four affected offspring of a consanguineous family with autosomal recessive moderate to profound NSHL without any vestibular or retinal dysfunction were investigated for molecular exploration of genes implicated in hearing impairment. Parallel to this study, we illustrate some possible pitfalls that resulted from unexpected allelic heterogeneity during homozygosity mapping due to identifying a shared homozygous region unrelated to the disease locus. Compound heterozygous missense variants (p.(Asp918Asn); p.(Val1670Asp)) in CDH23 were identified in affected patients by exome sequencing. Both the identified missense variants resulted in a substitution of the conserved residues and evaluation by multiple in silico tools predicted their pathogenicity and variable disruption of CDH23 domains. Three-dimensional structure analysis of human CDH23 confirmed that the residue Asp918 is located at a highly conserved DXD peptide motif and is directly involved in “Ca2+” ion contact. In conclusion, our study identifies pathogenic CDH23 variants responsible for isolated moderate to profound NSHL in Saudi patients and further highlights the associated phenotypic variability with a genotypic hierarchy of CDH23 mutations. The current investigation also supports the application of molecular testing in the clinical diagnosis and genetic counseling of hearing loss.
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10
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Whatley M, Francis A, Ng ZY, Khoh XE, Atlas MD, Dilley RJ, Wong EYM. Usher Syndrome: Genetics and Molecular Links of Hearing Loss and Directions for Therapy. Front Genet 2020; 11:565216. [PMID: 33193648 PMCID: PMC7642844 DOI: 10.3389/fgene.2020.565216] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/21/2020] [Indexed: 12/19/2022] Open
Abstract
Usher syndrome (USH) is an autosomal recessive (AR) disorder that permanently and severely affects the senses of hearing, vision, and balance. Three clinically distinct types of USH have been identified, decreasing in severity from Type 1 to 3, with symptoms of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP), and vestibular dysfunction. There are currently nine confirmed and two suspected USH-causative genes, and a further three candidate loci have been mapped. The proteins encoded by these genes form complexes that play critical roles in the development and maintenance of cellular structures within the inner ear and retina, which have minimal capacity for repair or regeneration. In the cochlea, stereocilia are located on the apical surface of inner ear hair cells (HC) and are responsible for transducing mechanical stimuli from sound pressure waves into chemical signals. These signals are then detected by the auditory nerve fibers, transmitted to the brain and interpreted as sound. Disease-causing mutations in USH genes can destabilize the tip links that bind the stereocilia to each other, and cause defects in protein trafficking and stereocilia bundle morphology, thereby inhibiting mechanosensory transduction. This review summarizes the current knowledge on Usher syndrome with a particular emphasis on mutations in USH genes, USH protein structures, and functional analyses in animal models. Currently, there is no cure for USH. However, the genetic therapies that are rapidly developing will benefit from this compilation of detailed genetic information to identify the most effective strategies for restoring functional USH proteins.
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Affiliation(s)
- Meg Whatley
- Ear Science Institute Australia, Nedlands, WA, Australia
| | - Abbie Francis
- Ear Science Institute Australia, Nedlands, WA, Australia
- Emergency Medicine, The University of Western Australia, Nedlands, WA, Australia
| | - Zi Ying Ng
- Ear Science Institute Australia, Nedlands, WA, Australia
| | - Xin Ee Khoh
- Ear Science Institute Australia, Nedlands, WA, Australia
- School of Human Sciences, The University of Western Australia, Nedlands, WA, Australia
| | - Marcus D. Atlas
- Ear Science Institute Australia, Nedlands, WA, Australia
- Ear Sciences Centre, The University of Western Australia, Nedlands, WA, Australia
| | - Rodney J. Dilley
- Ear Science Institute Australia, Nedlands, WA, Australia
- Ear Sciences Centre, The University of Western Australia, Nedlands, WA, Australia
- Centre for Cell Therapy and Regenerative Medicine, The University of Western Australia, Perth, WA, Australia
| | - Elaine Y. M. Wong
- Ear Science Institute Australia, Nedlands, WA, Australia
- Ear Sciences Centre, The University of Western Australia, Nedlands, WA, Australia
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, WA, Australia
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11
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Pardyak L, Kaminska A, Brzoskwinia M, Hejmej A, Kotula-Balak M, Jankowski J, Ciereszko A, Bilinska B. Differential expression of cell-cell junction proteins in the testis, epididymis, and ductus deferens of domestic turkeys (Meleagris gallopavo) with white and yellow semen. Poult Sci 2020; 99:555-566. [PMID: 32416842 PMCID: PMC7587856 DOI: 10.3382/ps/pez494] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 08/10/2019] [Indexed: 12/15/2022] Open
Abstract
Tight, adherens, and gap junctions are involved in the regulation of reproductive tissue function in male mammals. In birds, including domestic turkeys, intercellular interactions performed by junctional networks have not yet been studied. Furthermore, the cellular and molecular basis of yellow semen syndrome (YSS) in the turkey population remains poorly understood. Thus, the aim of the present study was 2-fold: first, to provide new information on the localization and expression of cell-cell junction proteins in the testis, epididymis, and ductus deferens of domestic turkeys and second, to compare expression of junctional protein genes between 2 turkey population, one that produces white normal semen (WNS) and the other that produces yellow abnormal semen. Expression of occludin, zonula occludens-1 (ZO-1), connexin 43 (Cx43), N- and E-cadherin, and β-catenin genes were investigated using 3 complementary techniques: quantitative real-time PCR, western blot, and immunohistochemistry. Compared to WNS testis, epididymis, and ductus deferens, YSS tissues exhibited downregulation of occludin and β-catenin mRNA (P < 0.05) and protein (P < 0.05 and P < 0.01, respectively) and upregulation of N- and E-cadherin mRNA (P < 0.001, P < 0.05, P < 0.01, respectively) and protein (P < 0.01, P < 0.05, and P < 0.05, respectively). In contrast, ZO-1 and Cx43 mRNA and protein were upregulated in YSS testis (P < 0.05 and P < 0.001, respectively) but not in epididymis and ductus deferens; both mRNAs and proteins were downregulated (P < 0.05) compared to the respective WNS epididymis and ductus deferens. Altered staining intensity of immunoreactive proteins in YSS vs. WNS reproductive tissue sections confirmed the gene expression results. The present study is the first to demonstrate altered levels of junctional protein gene expression in reproductive tissues of male YSS turkeys. These findings may suggest that subtle changes in junctional protein expression affect the microenvironment in which spermatozoa develop and mature and thus may have an impact on the appearance of yellow semen in domestic turkeys.
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Affiliation(s)
- L Pardyak
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland
| | - A Kaminska
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland
| | - M Brzoskwinia
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland
| | - A Hejmej
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland
| | - M Kotula-Balak
- University Centre of Veterinary Medicine, University of Agriculture in Krakow, 30-059 Krakow, Poland
| | - J Jankowski
- Department of Poultry Science, Faculty of Animal Bioengineering, University of Warmia and Mazury in Olsztyn, 10-957 Olsztyn, Poland
| | - A Ciereszko
- Department of Gamete and Embryo Biology, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-243 Olsztyn, Poland
| | - B Bilinska
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, 30-387 Krakow, Poland.
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12
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Massimiani M, Lacconi V, La Civita F, Ticconi C, Rago R, Campagnolo L. Molecular Signaling Regulating Endometrium-Blastocyst Crosstalk. Int J Mol Sci 2019; 21:E23. [PMID: 31861484 PMCID: PMC6981505 DOI: 10.3390/ijms21010023] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 11/29/2019] [Accepted: 12/16/2019] [Indexed: 12/13/2022] Open
Abstract
Implantation of the embryo into the uterine endometrium is one of the most finely-regulated processes that leads to the establishment of a successful pregnancy. A plethora of factors are released in a time-specific fashion to synchronize the differentiation program of both the embryo and the endometrium. Indeed, blastocyst implantation in the uterus occurs in a limited time frame called the "window of implantation" (WOI), during which the maternal endometrium undergoes dramatic changes, collectively called "decidualization". Decidualization is guided not just by maternal factors (e.g., estrogen, progesterone, thyroid hormone), but also by molecules secreted by the embryo, such as chorionic gonadotropin (CG) and interleukin-1β (IL-1 β), just to cite few. Once reached the uterine cavity, the embryo orients correctly toward the uterine epithelium, interacts with specialized structures, called pinopodes, and begins the process of adhesion and invasion. All these events are guided by factors secreted by both the endometrium and the embryo, such as leukemia inhibitory factor (LIF), integrins and their ligands, adhesion molecules, Notch family members, and metalloproteinases and their inhibitors. The aim of this review is to give an overview of the factors and mechanisms regulating implantation, with a focus on those involved in the complex crosstalk between the blastocyst and the endometrium.
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Affiliation(s)
- Micol Massimiani
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (M.M.); (V.L.); (F.L.C.)
- Saint Camillus International University of Health Sciences, Via di Sant’Alessandro, 8, 00131 Rome, Italy
| | - Valentina Lacconi
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (M.M.); (V.L.); (F.L.C.)
| | - Fabio La Civita
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (M.M.); (V.L.); (F.L.C.)
| | - Carlo Ticconi
- Department of Surgical Sciences, Section of Gynecology and Obstetrics, University Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy;
| | - Rocco Rago
- Physiopathology of Reproduction and Andrology Unit, Sandro Pertini Hospital, Via dei Monti Tiburtini 385/389, 00157 Rome, Italy;
| | - Luisa Campagnolo
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (M.M.); (V.L.); (F.L.C.)
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13
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Xu T, Zhu W, Wang P, Li H, Yu S. Identification of novel cadherin 23 variants in a Chinese family with hearing loss. Mol Med Rep 2019; 20:2609-2616. [PMID: 31322239 PMCID: PMC6691240 DOI: 10.3892/mmr.2019.10503] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 05/09/2019] [Indexed: 11/09/2022] Open
Abstract
The aim of the present study was to elucidate the role of the non-syndromic autosomal recessive deafness 12 allelic variant of cadherin 23 (CDH23) in Chinese patients with non-syndromic hearing loss. The present study focused on a Chinese family with hearing loss in which there were two siblings with autosomal, recessive deafness, ranging from severe to profound hearing loss over all frequencies. DNA sequencing was used to assess the genetic factors in the disease etiology. The data revealed a compound heterozygous mutation of CDH23 in both patients. Genetic CDH23 variants are known to be responsible for non-syndromic hearing loss, and CDH23 variants frequently occur in various populations, including Japanese and Republic of Korean. Results from the present study, indicated a significant contribution of CDH23 variants to the non-syndromic hearing loss in Chinese patients.
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Affiliation(s)
- Tianni Xu
- Department of Otolaryngology‑Head and Neck Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wei Zhu
- Department of Otolaryngology‑Head and Neck Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Ping Wang
- Department of Otolaryngology‑Head and Neck Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Haonan Li
- Department of Otolaryngology‑Head and Neck Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Shuyuan Yu
- Department of Otolaryngology‑Head and Neck Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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14
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Pan J, Yao Y, Guo X, Kong F, Zhou J, Meng X. Endoplasmic reticulum stress, a novel significant mechanism responsible for DEHP‐induced increased distance between seminiferous tubule of mouse testis. J Cell Physiol 2019; 234:19807-19823. [DOI: 10.1002/jcp.28580] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 02/27/2019] [Accepted: 03/06/2019] [Indexed: 01/12/2023]
Affiliation(s)
- Junlin Pan
- Shandong Provincial Key Laboratory of Animal Resistance Biology College of Life Sciences, Institute of Biomedical Sciences, Shandong Normal University Jinan Shandong China
| | - YuanYuan Yao
- Shandong Provincial Key Laboratory of Animal Resistance Biology College of Life Sciences, Institute of Biomedical Sciences, Shandong Normal University Jinan Shandong China
| | - Xiuxiu Guo
- Shandong Provincial Key Laboratory of Animal Resistance Biology College of Life Sciences, Institute of Biomedical Sciences, Shandong Normal University Jinan Shandong China
| | - Fengyun Kong
- Reproductive Medical Center The Second Hospital Affiliated to Shandong University of Traditional Chinese Medicine Jinan Shandong China
| | - Jun Zhou
- Shandong Provincial Key Laboratory of Animal Resistance Biology College of Life Sciences, Institute of Biomedical Sciences, Shandong Normal University Jinan Shandong China
| | - Xiaoqian Meng
- Shandong Provincial Key Laboratory of Animal Resistance Biology College of Life Sciences, Institute of Biomedical Sciences, Shandong Normal University Jinan Shandong China
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15
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Scarano WR, Pinho CF, Pissinatti L, Gonçalves BF, Mendes LO, Campos SG. Cell junctions in the prostate: an overview about the effects of Endocrine Disrupting Chemicals (EDCS) in different experimental models. Reprod Toxicol 2018; 81:147-154. [DOI: 10.1016/j.reprotox.2018.08.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 07/30/2018] [Accepted: 08/02/2018] [Indexed: 12/20/2022]
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16
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Hejmej A, Bilinska B. The effects of flutamide on cell-cell junctions in the testis, epididymis, and prostate. Reprod Toxicol 2018; 81:1-16. [PMID: 29958919 DOI: 10.1016/j.reprotox.2018.06.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 06/15/2018] [Accepted: 06/20/2018] [Indexed: 12/12/2022]
Abstract
In this review, we summarize recent findings on the effect of the anti-androgen flutamide on cell-cell junctions in the male reproductive system. We outline developmental aspects of flutamide action on the testis, epididymis, and prostate, and describe changes in junction protein expression and organization of junctional complexes in the adult boar following prenatal and postnatal exposure. We also discuss findings on the mechanisms by which flutamide induces alterations in cell-cell junctions in reproductive tissues of adult males, with special emphasis on cytoplasmic effects. Based on the results from in vivo and in vitro studies in the rat, we propose that flutamide affects the expression of junction proteins and junction complex structure not only by inhibiting androgen receptor activity, but equally important by modulating protein kinase-dependent signaling in testicular cells. Additionally, results from studies on prostate cancer cell lines point to a role for the cellular molecular outfit in response to flutamide.
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Affiliation(s)
- Anna Hejmej
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, Poland
| | - Barbara Bilinska
- Department of Endocrinology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, Poland.
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17
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Gao LR, Wang G, Zhang J, Li S, Chuai M, Bao Y, Hocher B, Yang X. High salt-induced excess reactive oxygen species production resulted in heart tube malformation during gastrulation. J Cell Physiol 2018; 233:7120-7133. [PMID: 29574800 DOI: 10.1002/jcp.26528] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Accepted: 01/31/2018] [Indexed: 12/30/2022]
Abstract
An association has been proved between high salt consumption and cardiovascular mortality. In vertebrates, the heart is the first functional organ to be formed. However, it is not clear whether high-salt exposure has an adverse impact on cardiogenesis. Here we report high-salt exposure inhibited basement membrane breakdown by affecting RhoA, thus disturbing the expression of Slug/E-cadherin/N-cadherin/Laminin and interfering with mesoderm formation during the epithelial-mesenchymal transition(EMT). Furthermore, the DiI+ cell migration trajectory in vivo and scratch wound assays in vitro indicated that high-salt exposure restricted cell migration of cardiac progenitors, which was caused by the weaker cytoskeleton structure and unaltered corresponding adhesion junctions at HH7. Besides, down-regulation of GATA4/5/6, Nkx2.5, TBX5, and Mef2c and up-regulation of Wnt3a/β-catenin caused aberrant cardiomyocyte differentiation at HH7 and HH10. High-salt exposure also inhibited cell proliferation and promoted apoptosis. Most importantly, our study revealed that excessive reactive oxygen species(ROS)generated by high salt disturbed the expression of cardiac-related genes, detrimentally affecting the above process including EMT, cell migration, differentiation, cell proliferation and apoptosis, which is the major cause of malformation of heart tubes.
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Affiliation(s)
- Lin-Rui Gao
- Division of Histology and Embryology, Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou, China.,Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou, China
| | - Guang Wang
- Division of Histology and Embryology, Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou, China.,Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou, China
| | - Jing Zhang
- Division of Histology and Embryology, Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou, China
| | - Shuai Li
- Division of Histology and Embryology, Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou, China
| | - Manli Chuai
- Division of Cell and Developmental Biology, University of Dundee, Dundee, UK
| | - Yongping Bao
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, UK
| | - Berthold Hocher
- Division of Histology and Embryology, Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou, China.,Institute of Nutritional Science, University of Potsdam, Potsdam-Nuthetal, Germany
| | - Xuesong Yang
- Division of Histology and Embryology, Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou, China.,Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou, China
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18
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Vanniya S P, Srisailapathy CRS, Kunka Mohanram R. The tip link protein Cadherin-23: From Hearing Loss to Cancer. Pharmacol Res 2018; 130:25-35. [PMID: 29421162 DOI: 10.1016/j.phrs.2018.01.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 01/24/2018] [Accepted: 01/26/2018] [Indexed: 11/26/2022]
Abstract
Cadherin-23 is an atypical member of the cadherin superfamily, with a distinctly long extracellular domain. It has been known to be a part of the tip links of the inner ear mechanosensory hair cells. Several studies have been carried out to understand the role of Cadherin-23 in the hearing mechanism and defects in the CDH23 have been associated with hearing impairment resulting from defective or absence of tip links. Recent studies have highlighted the role of Cadherin-23 in several pathological conditions, including cancer, suggesting the presence of several unknown functions. Initially, it was proposed that Cadherin-23 represents a yet unspecified subtype of Cadherins; however, no other proteins with similar characteristics have been identified, till date. It has a unique cytoplasmic domain that does not bear a β-catenin binding region, but has been demonstrated to mediate cell-cell adhesions. Several protein interacting partners have been identified for Cadherin-23 and the roles of their interactions in various cellular mechanisms are yet to be explored. This review summarizes the characteristics of Cadherin-23 and its roles in several pathologies including cancer.
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Affiliation(s)
- Paridhy Vanniya S
- Department of Genetics, Dr. ALM PG Institute of Basic Medical Science, University of Madras, Taramani campus, Chennai, Tamilnadu, India
| | - C R Srikumari Srisailapathy
- Department of Genetics, Dr. ALM PG Institute of Basic Medical Science, University of Madras, Taramani campus, Chennai, Tamilnadu, India
| | - Ramkumar Kunka Mohanram
- SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, Tamilnadu, India.
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19
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Kim SM, Kim JS. A Review of Mechanisms of Implantation. Dev Reprod 2017; 21:351-359. [PMID: 29359200 PMCID: PMC5769129 DOI: 10.12717/dr.2017.21.4.351] [Citation(s) in RCA: 165] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 12/06/2017] [Accepted: 12/08/2017] [Indexed: 01/09/2023]
Abstract
Implantation is a highly organized process that involves an interaction between a receptive uterus and a competent blastocyst. In humans, natural fecundity suggests that the chance of conception per cycle is relatively low (~30%) and two-third of lost pregnancies occur because of implantation failure. Defective implantation leads to adverse pregnancy outcomes including infertility, spontaneous miscarriage, intrauterine fetal growth restriction and preeclampsia. With use of advanced scientific technologies, gene expression analysis and genetically-engineered animal models have revealed critical cellular networks and molecular pathways. But, because of ethical restrictions and the lack of a mechanistic experiment, comprehensive steps in human implantation have still not been completely understood. This review primarily focuses on the recent advances in mechanisms of implantation. Because infertility is an emerging issue these days, gaining an understanding the molecular and hormonal signaling pathway will improve the outcome of natural pregnancy and assisted reproductive technology.
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Affiliation(s)
- Su-Mi Kim
- Dept. of Obstetrics and Gynecology, College of Medicine, Dankook
University, Cheonan 31116, Korea
| | - Jong-Soo Kim
- Dept. of Obstetrics and Gynecology, College of Medicine, Dankook
University, Cheonan 31116, Korea
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20
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De Cian MC, Pauper E, Bandiera R, Vidal VPI, Sacco S, Gregoire EP, Chassot AA, Panzolini C, Wilhelm D, Pailhoux E, Youssef SA, de Bruin A, Teerds K, Schedl A, Gillot I, Chaboissier MC. Amplification of R-spondin1 signaling induces granulosa cell fate defects and cancers in mouse adult ovary. Oncogene 2016; 36:208-218. [PMID: 27270435 PMCID: PMC5241429 DOI: 10.1038/onc.2016.191] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 02/26/2016] [Accepted: 04/21/2016] [Indexed: 12/16/2022]
Abstract
R-spondin1 is a secreted regulator of WNT signaling, involved in both embryonic development and homeostasis of adult organs. It can have a dual role, acting either as a mitogen or as a tumor suppressor. During ovarian development, Rspo1 is a key factor required for sex determination and differentiation of the follicular cell progenitors, but is downregulated after birth. In human, increased RSPO1 expression is associated with ovarian carcinomas, but it is not clear whether it is a cause or a consequence of the tumorigenic process. To address the role of Rspo1 expression in adult ovaries, we generated an Rspo1 gain-of-function mouse model. Females were hypofertile and exhibited various ovarian defects, ranging from cysts to ovarian tumors. Detailed phenotypical characterization showed anomalies in the ovulation process. Although follicles responded to initial follicle-stimulating hormone stimulation and developed normally until the pre-ovulatory stage, they did not progress any further. Although non-ovulated oocytes degenerated, the surrounding follicular cells did not begin atresia. RSPO1-induced expression not only promotes canonical WNT signaling but also alters granulosa cell fate decisions by maintaining epithelial-like traits in these cells. This prevents follicle cells from undergoing apoptosis, leading to the accumulation of granulosa cell tumors that reactivates the epithelial program from their progenitors. Taken together, our data demonstrate that activation of RSPO1 is sufficient in promoting ovarian tumors and thus supports a direct involvement of this gene in the commencement of ovarian cancers.
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Affiliation(s)
- M-C De Cian
- University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France.,EA 7310, Université de Corte, Corte, France
| | - E Pauper
- University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France
| | - R Bandiera
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - V P I Vidal
- University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France
| | - S Sacco
- University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France
| | - E P Gregoire
- University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France
| | - A-A Chassot
- University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France
| | - C Panzolini
- University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France
| | - D Wilhelm
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville Victoria, Australia
| | - E Pailhoux
- UMR BDR, INRA, ENVA, Université Paris Saclay, Jouy-en-Josas, France
| | - S A Youssef
- Department of Pathobiology, Faculty of Veterinary Medicine, Dutch Molecular Pathology Center, Utrecht University, Utrecht, The Netherlands
| | - A de Bruin
- Department of Pathobiology, Faculty of Veterinary Medicine, Dutch Molecular Pathology Center, Utrecht University, Utrecht, The Netherlands.,Department of Pediatrics, Division of Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - K Teerds
- Department of Human and Animal Physiology, Wageningen University, Wageningen, The Netherlands
| | - A Schedl
- University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France
| | - I Gillot
- University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France
| | - M-C Chaboissier
- University Nice Sophia Antipolis, Inserm, CNRS, iBV, Nice, France
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21
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Orfali GDC, Duarte AC, Bonadio V, Martinez NP, de Araújo MEMB, Priviero FBM, Carvalho PO, Priolli DG. Review of anticancer mechanisms of isoquercitin. World J Clin Oncol 2016; 7:189-199. [PMID: 27081641 PMCID: PMC4826964 DOI: 10.5306/wjco.v7.i2.189] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 10/19/2015] [Accepted: 02/16/2016] [Indexed: 02/06/2023] Open
Abstract
This review was based on a literature search of PubMed and Scielo databases using the keywords “quercetin, rutin, isoquercitrin, isoquercitin (IQ), quercetin-3-glucoside, bioavailability, flavonols and favonoids, and cancer” and combinations of all the words. We collected relevant scientific publications from 1990 to 2015 about the absorption, bioavailability, chemoprevention activity, and treatment effects as well as the underlying anticancer mechanisms of isoquercitin. Flavonoids are a group of polyphenolic compounds widely distributed throughout the plant kingdom. The subclass of flavonols receives special attention owing to their health benefits. The main components of this class are quercetin, rutin, and IQ, which is a flavonoid and although mostly found as a glycoside, is an aglycone (lacks a glycoside side chain). This compound presents similar therapeutic profiles to quercetin but with superior bioavailability, resulting in increased efficacy compared to the aglycone form. IQ has therapeutic applications owing to its wide range of pharmacological effects including antioxidant, antiproliferative, anti-inflammatory, anti-hypertensive, and anti-diabetic. The protective effects of IQ in cancer may be due to actions on lipid peroxidation. In addition, the antitumor effect of IQ and its underlying mechanism are related to interactions with Wnt signaling pathway, mixed-lineage protein kinase 3, mitogen-activated protein kinase, apoptotic pathways, as well proinflammatory protein signaling. This review contributed to clarifying the mechanisms of absorption, metabolism, and actions of IQ and isoquercitrin in cancer.
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22
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Dowland SN, Madawala RJ, Lindsay LA, Murphy CR. The adherens junction is lost during normal pregnancy but not during ovarian hyperstimulated pregnancy. Acta Histochem 2016; 118:137-43. [PMID: 26738975 DOI: 10.1016/j.acthis.2015.12.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 12/15/2015] [Accepted: 12/15/2015] [Indexed: 12/20/2022]
Abstract
During early pregnancy in the rat, the luminal uterine epithelial cells (UECs) must transform to a receptive state to permit blastocyst attachment and implantation. The implantation process involves penetration of the epithelial barrier, so it is expected that the transformation of UECs includes alterations in the lateral junctional complex. Previous studies have demonstrated a deepening of the tight junction (zonula occludens) and a reduction in the number of desmosomes (macula adherens) in UECs at the time of implantation. However, the adherens junction (zonula adherens), which is primarily responsible for cell-cell adhesion, has been little studied during early pregnancy. This study investigated the adherens junction in rat UECs during the early stages of normal pregnancy and ovarian hyperstimulated (OH) pregnancy using transmission electron microscopy. The adherens junction is present in UECs at the time of fertilisation, but is lost at the time of blastocyst implantation during normal pregnancy. Interestingly, at the time of implantation after OH, adherens junctions are retained and may impede blastocyst penetration of the epithelium. The adherens junction anchors the actin-based terminal web, which is known to be disrupted in UECs during early pregnancy. However, artificial disruption of the terminal web, using cytochalasin D, did not cause removal of the adherens junction in UECs. This study revealed that adherens junction disassembly occurs during early pregnancy, but that this process does not occur during OH pregnancy. Such disassembly does not appear to depend on the disruption of the terminal web.
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23
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Zhu G, Mao Y, Zhou W, Jiang Y. Dynamic Changes in the Follicular Transcriptome and Promoter DNA Methylation Pattern of Steroidogenic Genes in Chicken Follicles throughout the Ovulation Cycle. PLoS One 2015; 10:e0146028. [PMID: 26716441 PMCID: PMC4696729 DOI: 10.1371/journal.pone.0146028] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 12/11/2015] [Indexed: 12/17/2022] Open
Abstract
The molecular mechanisms associated with follicle maturation and ovulation are not well defined in avian species. In this study, we used RNA-seq to study the gene expression profiles of the chicken follicles from different developmental stages (pre-hierarchical, pre-ovulatory and post-ovulatory). Transcriptomic analysis revealed a total of 1,277 and 2,310 genes were differentially expressed when follicles progressed through the pre-hierarchical to hierarchical and pre-ovulatory to post-ovulatory transitions, respectively. The differentially expressed genes (DEG) were involved in signaling pathways such as adherens junction, apoptosis and steroid biosynthesis. We further investigated the transcriptional regulation of follicular steroidogenesis by examining the follicle-specific methylation profiles of Star (steroidogenic acute regulatory protein), Cyp11a1 (cytochrome P450, family 11, subfamily a, polypeptide 1) and Hsd3b (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1), genes encoding the key enzymes for progesterone synthesis. The varied patterns of DNA methylation in proximal promoters of Star and Cyp11a1but not Hsd3b in different follicles could play a major role in controlling gene expression as well as follicular steroidogenic activity. Finally, the promoter-reporter analysis suggests that TGF-β could be involved in the regulation of Hsd3b expression during ovulation. Together, current data not only provide novel insights into the molecular mechanisms of follicular physiology in chicken follicles, but also present the first evidence of epigenetic regulation of ovarian steroidogenesis in avian species.
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Affiliation(s)
- Guiyu Zhu
- Department of Biology Science and Technology, Taishan University, Taian 271021, China
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian 271018, China
| | - Yong Mao
- Department of Gynecology, Taian Materal and Child Health Hospital, Taian 271021, China
| | - Wendi Zhou
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian 271018, China
| | - Yunliang Jiang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian 271018, China
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Erol O, Süren D, Tutuş B, Toptaş T, Gökay AA, Derbent AU, Özel MK, Sezer C. Immunohistochemical Analysis of E-Cadherin, p53 and Inhibin-α Expression in Hydatidiform Mole and Hydropic Abortion. Pathol Oncol Res 2015; 22:515-21. [DOI: 10.1007/s12253-015-0031-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Accepted: 12/14/2015] [Indexed: 11/24/2022]
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25
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Minutoli L, Micali A, Pisani A, Puzzolo D, Bitto A, Rinaldi M, Pizzino G, Irrera N, Galfo F, Arena S, Pallio G, Mecchio A, Germanà A, Bruschetta D, Laurà R, Magno C, Marini H, Squadrito F, Altavilla D. Flavocoxid Protects Against Cadmium-Induced Disruption of the Blood–Testis Barrier and Improves Testicular Damage and Germ Cell Impairment in Mice [corrected]. Toxicol Sci 2015; 148:311-29. [PMID: 26424772 DOI: 10.1093/toxsci/kfv185] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Cadmium (Cd) causes male infertility. There is the need to identify safe treatments counteracting this toxicity. Flavocoxid is a flavonoid that induces a balanced inhibition of cyclooxygenase (COX)-1 and COX-2 peroxidase moieties and of 5-lipoxygenase (LOX) and has efficacy in the male genitourinary system. We investigated flavocoxid effects on Cd-induced testicular toxicity in mice. Swiss mice were divided into 4 groups: 2 control groups received 0.9% NaCl (vehicle; 1 ml/kg/day) or flavocoxid (20 mg/kg/day ip); 2 groups were challenged with cadmium chloride (CdCl2; 2 mg/kg/day ip) and administered with vehicle or flavocoxid. The treatment lasted for 1 or 2 weeks. The testes were processed for biochemical and morphological studies. CdCl2 increased phosphorylated extracellular signal-regulated kinase (p-ERK) 1/2, tumor necrosis factor (TNF)-α, COX-2, 5-LOX, malondialdehyde (MDA), B-cell-lymphoma (Bcl)-2-associated X protein (Bax), follicle-stimulating hormone (FSH), luteinizing hormone (LH), transforming growth factor (TGF) -β3, decreased Bcl-2, testosterone, inhibin-B, occludin, N-Cadherin, induced structural damages in the testis and disrupted the blood-testis barrier. Many TUNEL-positive germ cells and changes in claudin-11, occludin, and N-cadherin localization were present. Flavocoxid administration reduced, in a time-dependent way, p-ERK 1/2, TNF-α, COX-2, 5-LOX, MDA, Bax, FSH, LH, TGF-β3, augmented Bcl-2, testosterone, inhibin B, occludin, N-Cadherin, and improved the structural organization of the testis and the blood-testis barrier. Few TUNEL-positive germ cells were present and a morphological retrieval of the intercellular junctions was observed. In conclusion, flavocoxid has a protective anti-inflammatory, antioxidant, and antiapoptotic function against Cd-induced toxicity in mice testis. We suggest that flavocoxid may play a relevant positive role against environmental levels of Cd, otherwise deleterious to gametogenesis and tubular integrity.
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Affiliation(s)
| | - Antonio Micali
- Department of Biomedical Sciences and Morphological and Functional Images
| | - Antonina Pisani
- Department of Biomedical Sciences and Morphological and Functional Images
| | - Domenico Puzzolo
- Department of Biomedical Sciences and Morphological and Functional Images
| | | | | | | | | | | | - Salvatore Arena
- Department of Paediatric, Gynaecological Microbiological and Biomedical Sciences
| | | | - Anna Mecchio
- *Department of Clinical and Experimental Medicine
| | | | - Daniele Bruschetta
- Department of Biomedical Sciences and Morphological and Functional Images
| | - Rosaria Laurà
- Department of Biological and Environmental Sciences and
| | - Carlo Magno
- Department of Human Pathology, University of Messina, Messina, Italy
| | | | | | - Domenica Altavilla
- Department of Paediatric, Gynaecological Microbiological and Biomedical Sciences
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26
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Zarzycka M, Chojnacka K, Mruk D, Gorowska E, Hejmej A, Kotula-Balak M, Pardyak L, Bilinska B. Flutamide alters the distribution of c-Src and affects the N-cadherin-β-catenin complex in the seminiferous epithelium of adult rat. Andrology 2015; 3:569-81. [DOI: 10.1111/andr.12028] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 01/28/2015] [Accepted: 02/07/2015] [Indexed: 12/21/2022]
Affiliation(s)
- M. Zarzycka
- Department of Endocrinology; Institute of Zoology; Jagiellonian University; Krakow Poland
| | - K. Chojnacka
- Department of Endocrinology; Institute of Zoology; Jagiellonian University; Krakow Poland
| | - D.D. Mruk
- Center for Biomedical Research; Population Council; New York City New York USA
| | - E. Gorowska
- Department of Endocrinology; Institute of Zoology; Jagiellonian University; Krakow Poland
| | - A. Hejmej
- Department of Endocrinology; Institute of Zoology; Jagiellonian University; Krakow Poland
| | - M. Kotula-Balak
- Department of Endocrinology; Institute of Zoology; Jagiellonian University; Krakow Poland
| | - L. Pardyak
- Department of Endocrinology; Institute of Zoology; Jagiellonian University; Krakow Poland
| | - B. Bilinska
- Department of Endocrinology; Institute of Zoology; Jagiellonian University; Krakow Poland
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deCatanzaro D. Sex steroids as pheromones in mammals: the exceptional role of estradiol. Horm Behav 2015; 68:103-16. [PMID: 25125222 DOI: 10.1016/j.yhbeh.2014.08.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 07/31/2014] [Accepted: 08/04/2014] [Indexed: 12/18/2022]
Abstract
This article is part of a Special Issue (Chemosignals and Reproduction). Whether from endogenous or exogenous sources, 17β-estradiol (E2) has very powerful influences over mammalian female reproductive physiology and behavior. Given its highly lipophilic nature and low molecular mass, E2 readily enters excretions and can be absorbed from exogenous sources via nasal, cutaneous, and other modes of exposure. Indeed, systemic injection of tritiated estradiol ((3)H-E2) into a male mouse or bat has been shown to produce significant levels of radioactivity in the reproductive tissues and brain of cohabiting female conspecifics. Bioactive E2 and other steroids are naturally found in male mouse urine and other excretions, and males actively direct their urine at proximate females. Very low doses of E2 can mimic the Bruce effect (disruption of peri-implantation pregnancy by novel males), the Vandenbergh effect (early reproductive maturation induced by novel males), and male-induced estrus and ovulation. Males' capacities to induce the Bruce and Vandenbergh effects can both be diminished by manipulations that reduce their urinary E2. Uterine dynamics during the Bruce and Vandenbergh effects are consistent with the actions of E2. Collectively, these data demonstrate a critical role of male-sourced E2 in these major mammalian pheromonal effects.
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Affiliation(s)
- Denys deCatanzaro
- Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
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Zhang H, Du B, Yang Y, Higginson DM, Carrière Y, Wu Y. Cadherin mutation linked to resistance to Cry1Ac affects male paternity and sperm competition in Helicoverpa armigera. JOURNAL OF INSECT PHYSIOLOGY 2014; 70:67-72. [PMID: 25220924 PMCID: PMC4334375 DOI: 10.1016/j.jinsphys.2014.08.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2014] [Revised: 07/20/2014] [Accepted: 08/19/2014] [Indexed: 05/14/2023]
Abstract
Several lepidopteran pests of cotton have cadherin-based resistance to the Bacillus thuringiensis (Bt) toxin Cry1Ac. Cadherins are transmembrane proteins that mediate cell-cell adhesion and tissue morphogenesis, suggesting that fitness costs associated with cadherin mutations may be present in many aspects of life history. To evaluate whether cadherin-based resistance is associated with fitness costs reducing male paternity in Helicoverpa armigera, we examined the effects of a major cadherin resistance allele on sperm competition within and between male ejaculates. When homozygous resistant and susceptible males competed for fertilization of a homozygous resistant or susceptible female, fertilization success was high in males with a different cadherin genotype than females, and low in males with the same cadherin genotype as females. Single matings between heterozygous males and susceptible females produced offspring within typical Mendelian ratios. Heterozygous males mated to resistant females, however, resulted in a disproportionate number of heterozygous offspring. While these results show that cadherin-based resistance to Cry1Ac has significant impacts on paternity in H. armigera, there was no evidence that costs associated with resistance consistently reduced male paternity. Rather, effects of cadherin-based resistance on paternity depended on interactions between male and female genotypes and differed when males or sperm competed for fertilization of females, which complicates assessment of impacts of cadherin resistance alleles on resistance evolution.
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Affiliation(s)
- Haonan Zhang
- College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China
| | - Bing Du
- College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China
| | - Yihua Yang
- College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China
| | - Dawn M Higginson
- Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, AZ, USA; Center for Insect Science, University of Arizona, Tucson, USA
| | - Yves Carrière
- Center for Insect Science, University of Arizona, Tucson, USA; Department of Entomology, University of Arizona, Tucson, AZ, USA
| | - Yidong Wu
- College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China
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29
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Ko SY, Naora H. HOXA9 promotes homotypic and heterotypic cell interactions that facilitate ovarian cancer dissemination via its induction of P-cadherin. Mol Cancer 2014; 13:170. [PMID: 25023983 PMCID: PMC4105245 DOI: 10.1186/1476-4598-13-170] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2014] [Accepted: 07/04/2014] [Indexed: 12/30/2022] Open
Abstract
Background Epithelial ovarian cancer (EOC) is a lethal disease that frequently involves the peritoneal cavity. Dissemination of EOC is a multi-step process in which exfoliated tumor cells survive in the peritoneal fluid as multi-cellular aggregates and then form invasive implants on peritoneal surfaces. The mechanisms that control this process are poorly understood. We previously identified that high expression of the developmental patterning gene HOXA9 is associated with poor survival in EOC patients. In this study, we investigated the significance and mechanisms of HOXA9 in controlling aggregation and implantation of floating EOC cells. Methods HOXA9 was inhibited by shRNAs or expressed in EOC cells that were propagated in suspension cultures and in the peritoneal cavity of mice. Cell death was assayed by flow cytometry and ELISA. Cell aggregation, attachment and migration were evaluated by microscopy, transwell chamber assays and histopathologic analysis. DNA-binding of HOXA9 and its effect on expression of the cell adhesion molecule P-cadherin were assayed by chromatin immunoprecipitation, quantitative RT-PCR and Western blot. HOXA9 and P-cadherin expression was evaluated in publicly available datasets of EOC clinical specimens. Results We identified that HOXA9 promotes aggregation and inhibits anoikis in floating EOC cells in vitro and in xenograft models. HOXA9 also stimulated the ability of EOC cells to attach to peritoneal cells and to migrate. HOXA9 bound the promoter of the CDH3 gene that encodes P-cadherin, induced CDH3 expression in EOC cells, and was associated with increased CDH3 expression in clinical specimens of EOC. Inhibiting P-cadherin in EOC cells that expressed HOXA9 abrogated the stimulatory effects of HOXA9 on cell aggregation, implantation and migration. Conversely, these stimulatory effects of HOXA9 were restored when P-cadherin was reconstituted in EOC cells in which HOXA9 was inhibited. Conclusion These findings indicate that HOXA9 contributes to poor outcomes in EOC in part by promoting intraperitoneal dissemination via its induction of P-cadherin.
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Affiliation(s)
| | - Honami Naora
- Department of Molecular & Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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30
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Rajabi N, Thorpe JB, Foster WG, deCatanzaro D. Novel male exposure reduces uterine e-cadherin, increases uterine luminal area, and diminishes progesterone levels while disrupting blastocyst implantation in inseminated mice. J Steroid Biochem Mol Biol 2014; 139:107-13. [PMID: 23962793 DOI: 10.1016/j.jsbmb.2013.08.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Revised: 07/30/2013] [Accepted: 08/05/2013] [Indexed: 10/26/2022]
Abstract
Exposure to novel male mice disrupts blastocyst implantation in inseminated female mice, and evidence increasingly implicates the female's absorption of male urinary estrogens. We observed implantation sites in male-exposed and isolated control female mice during gestation days (GD) 2-8, observing a significant reduction in male-exposed females compared to controls, particularly on GD 6 and 8. We also measured transitions in uterine luminal area and e-cadherin expression, as these processes are modulated by estrogens. Luminal area was greater in male-exposed females than in controls during the post-implantation period (GD 5-7). E-cadherin levels were suppressed by male exposure, particularly during GD 4-6 Serum progesterone levels were also reduced in male-exposed females. The effects of male exposure on uterine closure and e-cadherin levels are consistent with established effects of estrogens, and suggest a possible mechanism that could contribute to implantation failure. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.
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Affiliation(s)
- Nazanin Rajabi
- Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, Ontario L8S 4K1, Canada
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31
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Gorowska E, Zarzycka M, Chojnacka K, Bilinska B, Hejmej A. Postnatal exposure to flutamide affects CDH1 and CTNNB1 gene expression in adult pig epididymis and prostate and alters metabolism of testosterone. Andrology 2013; 2:186-97. [PMID: 24353261 DOI: 10.1111/j.2047-2927.2013.00172.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Revised: 11/04/2013] [Accepted: 11/18/2013] [Indexed: 12/01/2022]
Abstract
In both epididymis and prostate the dynamic cross-talk between the cells is hormonally regulated and, in part, through direct cell-to-cell interactions. Functionality of the male reproductive organs may be affected by exposure to specific chemicals, so-called 'reprotoxicants'. In this study we tested whether early postnatal and prepubertal exposure to anti-androgen flutamide altered the expression of adherens junction genes encoding E-cadherin (CDH1) and β-catenin (CTNNB1) in adult pig epididymis and prostate. In addition, the expression of mRNAs and proteins for 5α-reductase (ST5AR2) and aromatase (CYP19A1) were examined to show whether flutamide alters metabolism of testosterone. Thus, flutamide was injected into male piglets between Days 2 and 10 and between Days 90 and 98 postnatally (PD2 and PD90; 50 mg/kg bw), tissues that were obtained on postnatal Day 270. To assess the expression of the genes and proteins, real-time RT-PCR and Western blot were performed respectively. Moreover, adherens junction proteins were localized by immunohistochemistry. In response to flutamide, CDH1 and CTNNB1 expressions were down-regulated along the epididymis, mostly in PD2 group (p < 0.001, p < 0.01). In the prostate, CDH1 mRNA and protein expressions were significantly down-regulated (p < 0.01), whereas CTNNB1 mRNA was slightly up-regulated in both flutamide-treated groups. CTNNB1 protein level was markedly elevated in both PD2 (p < 0.001) and PD90 (p < 0.01) groups. In the epididymis, the expression of ST5AR2 and CYP19A1 was down- and up-regulated, respectively (p < 0.05), whereas in the prostate evident decrease in CYP19A1 expression (p < 0.001, p < 0.01, p < 0.05) was demonstrated. In both tissues, membranous immunolocalization of CTNNB1 suggests its involvement in cell-cell adhesion. Overall, flutamide administration resulted in suppression of androgen action in the epididymis and prostate leading to deregulation of CDH1 and CTNNB1 gene expressions which is probably caused by the alterations in the expression of ST5AR2 and CYP19A1 in both reproductive organs.
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Affiliation(s)
- E Gorowska
- Department of Endocrinology, Institute of Zoology, Jagiellonian University, Krakow, Poland
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Ohira T, Murayama C, Shimizu T, Yoshimura Y, Isobe N. Comparison of cadherin and integrin localization in bovine cystic and healthy follicles. Anim Sci J 2012; 84:303-9. [PMID: 23590503 DOI: 10.1111/asj.12008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Accepted: 08/13/2012] [Indexed: 11/30/2022]
Abstract
As stage progresses in the cystic follicle, granulosa cells are lost. We hypothesized that the granulosa and theca interna layers are detached in association with weakened expression of cell adhesion molecules such as cadherin (cell-cell adhesion) and integrin (cell-extracellular matrix adhesion) in cystic follicles. To elucidate this hypothesis, we immunolocalized these molecules in the granulosa and theca interna and compared them between cystic and small healthy follicles. Sections were immunostained with cadherin and integrin β1 antibodies and their localizations were compared. Cadherin-positive reaction was seen in the cytoplasma of all granulosa cells. No increase in the frequency of cadherin-positive area in the granulosa layers and the intensity of cadherin immunoreaction in the theca interna was detected in cystic follicles compared with healthy ones. A dense immunoreaction product of integrin β1 was detected in the theca interna in both cystic and healthy follicles. Intensity of integrin β1 -immuno reaction in the granulosa layers and integrin β1 -positive area in the theca interna was significantly lower in the cystic follicle than in the healthy follicles. These results suggest that granulosa and theca interna cells are detached while maintaining the cell-cell adhesion, resulting in the consequent loss of these layers from the cystic follicle.
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Affiliation(s)
- Tomomi Ohira
- Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
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Fleming A, Ghahramani N, Zhu MX, Délot EC, Vilain E. Membrane β-catenin and adherens junctions in early gonadal patterning. Dev Dyn 2012; 241:1782-98. [PMID: 22972715 DOI: 10.1002/dvdy.23870] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2012] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Mechanisms involved in early patterning of the mammalian gonad as it develops from a bipotential state into a testis or an ovary are as yet not well understood. Sex-specific vascularization is essential in this process, but more specific mechanisms required to, for example, establish interstitial vs. cord compartments in the testis or ovigerous cords in the ovary have not been reported. Adherens junctions (AJs) are known for their roles in morphogenesis; we, therefore, examined expression of AJ components including β-catenin, p120 catenin, and cadherins for possible involvement in sex-specific patterning of the gonad. RESULTS We show that, at the time of early gonadal sex differentiation, membrane-associated β-catenin and p120 catenin colocalize with cell-specific cadherins in both sex-nonspecific and sex-specific patterns. These expression patterns are consistent with an influence of AJs in overall patterning of the testis vs. ovary through known AJ mechanisms of cell-cell adhesion, cell sorting, and boundary formation. CONCLUSIONS Together these complex and dynamic patterns of AJ component expression precisely mirror patterning of tissues during gonadogenesis and raise the possibility that AJs are essential effectors of patterning within the developing testis and ovary.
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Affiliation(s)
- Alice Fleming
- Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, CA 90095, USA
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Miyagawa M, Nishio SY, Usami SI. Prevalence and clinical features of hearing loss patients with CDH23 mutations: a large cohort study. PLoS One 2012; 7:e40366. [PMID: 22899989 PMCID: PMC3416829 DOI: 10.1371/journal.pone.0040366] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2012] [Accepted: 06/04/2012] [Indexed: 12/31/2022] Open
Abstract
Screening for gene mutations in CDH23, which has many exons, has lagged even though it is likely to be an important cause for hearing loss patients. To assess the importance of CDH23 mutations in non-syndromic hearing loss, two-step screening was applied and clinical characteristics of the patients with CDH23 mutations were examined in this study. As a first screening, we performed Sanger sequencing using 304 probands compatible with recessive inheritance to find the pathologic mutations. Twenty-six possible mutations were detected to be pathologic in the first screening. For the second screening, using the probes for these 26 mutations, a large cohort of probands (n = 1396) was screened using Taqman amplification-based mutation analysis followed by Sanger sequencing. The hearing loss in a total of 52 families (10 homozygous, 13 compound heterogygous, and 29 heterozygous) was found to be caused by the CDH23 mutations. The majority of the patients showed congenital, high frequency involved, progressive hearing loss. Interestingly, some particular mutations cause late onset moderate hearing loss. The present study is the first to demonstrate the prevalence of CDH23 mutations among non-syndromic hearing loss patients and indicated that mutations of the CDH23 gene are an important cause of non-syndromic hearing loss.
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Affiliation(s)
- Maiko Miyagawa
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shin-ya Nishio
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shin-ichi Usami
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan
- * E-mail:
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Vunnam N, Pedigo S. X-interface is not the explanation for the slow disassembly of N-cadherin dimers in the apo state. Protein Sci 2012; 21:1006-14. [PMID: 22544613 DOI: 10.1002/pro.2083] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2012] [Revised: 04/11/2012] [Accepted: 04/18/2012] [Indexed: 11/09/2022]
Abstract
In spite of structural similarities Epithelial- (E-) and Neural- (N-) cadherins are expressed at two types of synapses and differ significantly in dimer disassembly kinetics. Recent studies suggested that the formation of an X-dimer intermediate in E-cadherin is the key requirement for rapid disassembly of the adhesive dimer (Harrison et al., Nat Struct Mol Biol 2010;17:348-357 and Hong et al., J Cell Biol 2011;192:1073-1083). The X-interface in E-cadherin involves three noncovalent interactions, none of which is conserved in N-cadherin. Dimer disassembly is slow at low calcium concentration in N-cadherin, which may be due to the differences in the X-interface residues. To investigate the origin of the slow disassembly kinetics we introduced three point mutations into N-cadherin to provide the opportunity for the formation of X-interface interactions. Spectroscopic studies showed that the triple mutation did not affect the stability or the calcium-binding affinity of the X-enabled N-cadherin mutant. Analytical size exclusion chromatography was used to assay for the effect of the mutation on the rate of dimer disassembly. Contrary to our expectation, the disassembly of dimers of the X-enabled N-cadherin mutant was as slow as seen for wild-type N-cadherin in the apo-state. Thus, the differences in the X-interface residues are not the origin of slow disassembly kinetics of N-cadherin in the apo-state.
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Affiliation(s)
- Nagamani Vunnam
- Department of Chemistry and Biochemistry, University of Mississippi, University, Mississippi 38677, USA
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Vunnam N, Pedigo S. Sequential binding of calcium leads to dimerization in neural cadherin. Biochemistry 2011; 50:2973-82. [PMID: 21366346 DOI: 10.1021/bi101872b] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Neural cadherin (N-cadherin) is a calcium-dependent homophilic cell-adhesive molecule and critical for synaptogenesis and synapse maintenance. The extracellular region plays an important role in cadherin-mediated cell adhesion and has five tandemly repeated ectodomains (EC1-EC5) with three calcium-binding sites situated between each of these domains. Adhesive dimer formation is significantly dependent on binding of calcium such that mutations in the calcium-binding sites adversely affect cell adhesion. To investigate the relative significance of the calcium-binding sites at the EC1-EC2 interface in calcium-induced dimerization, we mutated three important amino acids, D134, D136, and D103, in NCAD12, a construct containing EC1 and EC2. Spectroscopic and chromatographic experiments showed that all three mutations affected calcium binding and dimerization. Mutation of D134, a bidentate chelator in site 3, severely impaired the binding of calcium to all three sites. These findings confirm that binding to site 3 is required for binding to occur at site 2 and site 1. Interestingly, while the D103A mutation diminished only the affinity for calcium, it completely eliminated dimerization. Equilibrium dialysis experiments showed a stoichiometry of 3 at 2 mM calcium for D103A, but no dimerization was apparent even at 10 mM calcium. These results indicate that calcium binding alone is not sufficient for dimerization but requires cooperativity between calcium-binding sites. In summary, our findings confirm that the calcium-binding sites are occupied sequentially in the order of site 3, then site 2 and site 1, and that cooperativity between site 2 and site 1 is essential for formation of adhesive dimers by N-cadherin.
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Affiliation(s)
- Nagamani Vunnam
- Department of Chemistry and Biochemistry, University of Mississippi, University, Mississippi 38677, United States
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Ben Chedly H, Boutinaud M, Bernier-Dodier P, Marnet PG, Lacasse P. Disruption of cell junctions induces apoptosis and reduces synthetic activity in lactating goat mammary gland. J Dairy Sci 2010; 93:2938-51. [DOI: 10.3168/jds.2009-2678] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2009] [Accepted: 03/19/2010] [Indexed: 11/19/2022]
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McEwan M, Lins RJ, Munro SK, Vincent ZL, Ponnampalam AP, Mitchell MD. Cytokine regulation during the formation of the fetal-maternal interface: focus on cell-cell adhesion and remodelling of the extra-cellular matrix. Cytokine Growth Factor Rev 2009; 20:241-9. [PMID: 19487153 DOI: 10.1016/j.cytogfr.2009.05.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The establishment of human pregnancy requires the orchestration of substantial cell differentiation and tissue remodelling processes in the context of a complex dialogue between the receptive endometrium and the implanting blastocyst, and is therefore dependent upon a complex sequence of signalling events. Cytokines play an important role in each step of implantation, modulating expression of adhesion molecules on both the fetal and maternal surfaces, regulating expression of the proteases that remodel the extra-cellular matrix, and promoting invasion and differentiation of trophoblasts. Here we review the role of cytokines in regulating the establishment of the fetal-maternal interface, with a particular focus on regulation of the functional expression of CAMs, the ECM and of the proteinases that modulate their function.
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Affiliation(s)
- Miranda McEwan
- The Liggins Institute and National Research Centre for Growth and Reproduction, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
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Smith SR, Fulton N, Collins CS, Welsh M, Bayne RAL, Coutts SM, Childs AJ, Anderson RA. N- and E-cadherin expression in human ovarian and urogenital duct development. Fertil Steril 2009; 93:2348-53. [PMID: 19324354 DOI: 10.1016/j.fertnstert.2009.01.113] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2008] [Revised: 01/13/2009] [Accepted: 01/19/2009] [Indexed: 11/13/2022]
Abstract
OBJECTIVE To investigate expression of N- and E-cadherin in the developing human ovary. DESIGN The expression of N- and E-cadherin was analyzed in 18 human fetal ovaries between 8 and 20 weeks' gestation using immunohistochemistry. Fetal human male and rat urogenital tracts were used for comparison of expression. SETTING Academic research institute. PATIENT(S) Women undergoing termination of pregnancy. INTERVENTION(S) Immunofluorescent analysis of cadherin expression. RESULT(S) In fetal ovary, N- and E-cadherins were expressed at all gestations with overlapping but not identical patterns. Expression was associated with germ cells and adjacent somatic cells, including within newly formed primordial follicles, but neither cadherin was expressed in the somatic cell cords. The epithelia of the müllerian and wolffian ducts expressed only N- and E-cadherin, respectively, in a mutually exclusive fashion. This pattern of cadherin expression was found to be conserved between human and rat fetuses of both genders. CONCLUSION(S) The demonstration of N- and E-cadherin expression in the human fetal ovary indicates likely roles in gonadal development from germ cell proliferation to primordial follicle formation, as well as in the development of the urogenital ducts of both genders. This is consistent with animal studies identifying cadherins as key regulators of early germ cell development.
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Affiliation(s)
- Sarah R Smith
- Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, University of Edinburgh, Edinburgh EH16 4TJ, Scotland
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Oshima A, Jaijo T, Aller E, Millan JM, Carney C, Usami S, Moller C, Kimberling WJ. Mutation profile of the CDH23 gene in 56 probands with Usher syndrome type I. Hum Mutat 2008; 29:E37-46. [PMID: 18429043 DOI: 10.1002/humu.20761] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Mutations in the human gene encoding cadherin23 (CDH23) cause Usher syndrome type 1D (USH1D) and nonsyndromic hearing loss. Individuals with Usher syndrome type I have profound congenital deafness, vestibular areflexia and usually begin to exhibit signs of RP in early adolescence. In the present study, we carried out the mutation analysis in all 69 exons of the CDH23 gene in 56 Usher type 1 probands already screened for mutations in MYO7A. A total of 18 of 56 subjects (32.1%) were observed to have one or two CDH23 variants that are presumed to be pathologic. Twenty one different pathologic genome variants were observed of which 15 were novel. Out of a total of 112 alleles, 31 (27.7%) were considered pathologic. Based on our results it is estimated that about 20% of patients with Usher syndrome type I have CDH23 mutations.
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Affiliation(s)
- A Oshima
- Center for the Study and Treatment of Usher Syndrome, Boys Town National research hospital, Omaha, Nebraska 68131, USA
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Arom KV, Ruengsakulrach P, Jotisakulratana V. Efficacy of Intramyocardial Injection of Angiogenic Cell Precursors for Ischemic Cardiomyopathy. INNOVATIONS-TECHNOLOGY AND TECHNIQUES IN CARDIOTHORACIC AND VASCULAR SURGERY 2008. [DOI: 10.1177/155698450800300109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Kitipan V. Arom
- Division of Cardiovascular Surgery, Bangkok Heart Hospital, Bangkok, Thailand
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Efficacy of intramyocardial injection of angiogenic cell precursors for ischemic cardiomyopathy: a case match study. INNOVATIONS-TECHNOLOGY AND TECHNIQUES IN CARDIOTHORACIC AND VASCULAR SURGERY 2008; 3:38-45. [PMID: 22436722 DOI: 10.1097/imi.0b013e31816755dd] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
INTRODUCTION : The objective of this study is to determine the efficacy of intramyocardial angiogenic cell precursors (ACPs) injection in ischemic cardiomyopathy (ICM). METHODS : Twenty-five ICM patients (cell group) underwent intramyocardial ACPs injection. Seventeen ICM patients (control group) treated by medical means were matched with cell group. There was no statistically significant difference between cell and control groups in relation to left ventricular ejection fraction (LVEF) and comorbidities. In the cell group, mean age was 58.4 ± 13.7 years. Mean LVEF was 26.1% ± 7.4%. New York Heart Association (NYHA) class was 2.9 ± 0.6. The ACPs were derived and expanded from autologous blood. The number of cells before injection was 27.4 ± 18.8 million cells. The cells were injected into the nonviable myocardium and hypokinetic segments in the cell group. RESULTS : There was no new ventricular arrhythmia. NYHA was improved by 0.9 ± 1.0 (P < 0.001) at 229.9 ± 98.8 days. Six-minute walk test and quality of life assessed by short form-36 improved in the cell group. LVEF was improved in 72% of patients (18 of 25). LVEF improved by 6.4 ± 9.9 points % (P = 0.003) at 290.4 ± 210.3 days. The percentage of infarction area decreased 21.9 ± 17.4 points % at 159 ± 54 days postoperatively. There was no significant improvement of NYHA and LVEF in the control group. CONCLUSIONS : For this efficacy study, the NYHA class, quality of life, and six-minute walk test were improved after cell transplantation. The LVEF was also significantly improved in the cell treated group.
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Pospechova K, Kopecky M, Nachtigal P, Pospisilova N, Jamborova G, Semecky V. Changes in the expression of P-cadherin in the normal, cryptorchid and busulphan-treated rat testis. ACTA ACUST UNITED AC 2007; 30:430-8. [PMID: 17298545 DOI: 10.1111/j.1365-2605.2006.00738.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Adhesion between Sertoli cells and germ cells is important for spermatogenesis. Cadherins are Ca(2+)-dependent transmembrane proteins that mediate cell-cell adhesion. The aim of this study was to compare the expression of P-cadherin in unilaterally cryptorchid and busulphan-treated rat testes using immunohistochemistry. The pattern of expression of P-cadherin in the seminiferous epithelium changed with the stage of the seminiferous epithelium. The membranes of round spermatids and membranes and cytoplasm of spermatocytes were strongly positive. Our experiments revealed that busulphan treatment (2 doses - 10 mg/kg of body weight - 21 days apart) and cryptorchism led to destructive changes in the structure of seminiferous tubules, together with the decrease in P-cadherin expression. The expression of P-cadherin disappeared in the spermatids segregated from the epithelium while segregated spermatocytes remained still positive for P-cadherin during the 3- to 11-day cryptorchid period. In busulphan-treated animals, the expression of P-cadherin was dependent on the presence or absence of the spermatocytes and spermatids in the tubules. Strong positivity for P-cadherin was observed in the spermatocytes that re-appeared in the regenerating seminiferous epithelium. We suggest that P-cadherin participates in the architecture of adherens junctions in testis, plays an important role in maintaining normal spermatogenesis and that cryptorchism and busulphan treatment lead to adherens junction disintegration.
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Affiliation(s)
- K Pospechova
- Department of Biological and Medical Sciences, Faculty of Pharmacy, Charles University, Hradec Kralove, Czech Republic.
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Abal M, Llauradó M, Doll A, Monge M, Colas E, González M, Rigau M, Alazzouzi H, Demajo S, Castellví J, García A, Ramón y Cajal S, Xercavins J, Vázquez-Levin MH, Alameda F, Gil-Moreno A, Reventos J. Molecular determinants of invasion in endometrial cancer. Clin Transl Oncol 2007; 9:272-7. [PMID: 17525037 DOI: 10.1007/s12094-007-0054-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Endometrial carcinoma is the most common gynaecological malignancy in the western world and the most frequent among infiltrating tumours of the female genital tract. Despite the characterisation of molecular events associated with the development of endometrial carcinoma, those associated with the early steps of infiltration and invasion in endometrial cancer are less known. Deep myometrial invasion correlates with more undifferentiated tumours, lymph-vascular invasion, node affectation and decreased global survival. In this review we present an overview of the molecular pathology of myometrial infiltration that defines the initial steps of invasion in endometrial cancer. Down-regulation of E-cadherin as a main player of epithelial to mesenchymal transition, as well as modifications on other molecules involved in cell-cell contacts, render cells with a migratory phenotype. In addition, altered signalling pathways and transcription factors associate with myometrial invasion, histologic grade and metastasis.
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Affiliation(s)
- M Abal
- Biomedical Research Unit, Research Institute Vall d'Hebron University Hospital, Barcelona, Spain.
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Yasmeen A, Bismar TA, Al Moustafa AE. ErbB receptors and epithelial-cadherin-catenin complex in human carcinomas. Future Oncol 2007; 2:765-81. [PMID: 17155902 DOI: 10.2217/14796694.2.6.765] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The ErbB family of receptor tyrosine kinases have important roles in maintaining normal epithelial cell function. The ErbBs are involved in the interaction between cells and cell-matrix adhesion molecules and have proven critical in maintaining the integrity of the epithelial cell environment. Deregulation of these tyrosine receptors has been associated with several human diseases. In particular, the expression or activation of epidermal growth factor receptor (EGFR) and ErbB2 is altered in many epithelial tumors. Epithelial (E)-cadherin is another major molecule expressed by epithelial cells. To create efficient cell-cell adhesion, E-cadherin couples its cytoplasmic domain to catenins and the actin cytoskeleton. The loss of intercellular adhesion appears to be a fundamental aspect of the neoplastic phenomena. In addition, EGFR and ErbB2 signaling associated with the E-cadherin-catenin complex has been demonstrated in normal and cancer cells. This signaling is involved in regulating cell adhesion and the invasive growth of cancers. This article provides an overview of the interaction between the ErbB tyrosine receptors and the E-cadherin-catenin complex in human carcinomas.
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Affiliation(s)
- Amber Yasmeen
- McGill University, Program in Cancer Genetics, Department of Oncology, Montreal, Quebec, Canada.
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Baravalle C, Salvetti NR, Mira GA, Pezzone N, Ortega HH. Microscopic characterization of follicular structures in letrozole-induced polycystic ovarian syndrome in the rat. Arch Med Res 2006; 37:830-9. [PMID: 16971221 DOI: 10.1016/j.arcmed.2006.04.006] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2005] [Accepted: 04/24/2006] [Indexed: 02/08/2023]
Abstract
BACKGROUND Our objective was to characterize the tissular distribution of relevant cytoskeletal proteins, cellular adhesion molecules and proliferation markers and conduct a histomorphometrical study of the follicular wall of letrozole-induced polycystic ovaries. METHODS Twenty rats were divided into two groups: a control group (C) of ten rats that received vehicle only (0.9% NaCl solution) once daily p.o. and a treatment group (T) of ten animals administered letrozole at a concentration of 1 mg/kg p.o. dissolved in 0.9% NaCl solution once daily during 21 days. Twenty four h after the last administration, all animals were sacrificed. Control animals were sacrificed in proestrous (n = 5) and diestrous (n = 5). Serum hormone levels, histomorphometrical changes and immunoexpression of intermediate filaments (vimentin, cytokeratins and desmin), cadherins and proliferation cellular nuclear antigen were examined. RESULTS The granulosa cell layer of cystic follicles had a greater significant immunostaining for vimentin and cytokeratins. Immunohistochemical localization of desmin was restricted to the theca externa. Positive immunoreactivity for cadherins rises gradually and significantly, together with the follicular development, and immunoreactivity was comparatively stronger in follicular cysts. A significantly higher immunostaining for PCNA cells was observed in secondary and tertiary follicles as compared with atretic and cystic follicles. An increase in the LH, FSH and testosterone serum concentrations was observed in letrozole-treated rats. Estradiol and progesterone showed a considerable reduction. CONCLUSIONS The changes observed are probably due to structural and functional alterations that occur during the process of cystogenesis and may be associated with important modifications in the expression of cytoskeletal proteins, cellular adhesion molecules and proliferation markers that may be essential for proper cellular functioning.
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Affiliation(s)
- Celina Baravalle
- Department of Anatomy and Histology, Faculty of Veterinary Sciences, National University of Litoral, Esperanza, Santa Fe, Argentina
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Prisco M, Liguoro A, Ricchiari L, Angelini F, Andreuccetti P. Cadherin in developing and maturing cysts of Torpedo Marmorata
Testis. Mol Reprod Dev 2006; 74:242-8. [PMID: 16955403 DOI: 10.1002/mrd.20517] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
We investigated the presence of cadherins, Ca++ dependent cell-cell adhesion molecules, during the development and maturation of cysts in the testis of the spotted ray Torpedo marmorata. Using different anti-cadherin antibodies, we provide evidence by means of immunohistochemistry and immunoblotting that cadherins are involved in the interaction between Sertoli and germ cells. During the development and maturation of cysts, in fact, cadherins occur between Sertoli and germ cells when they begin to interact to build a cyst. Later on, the presence of cadherins between Sertoli and germ cells persists; furthermore, during the formation of spermatoblast, it is also evident at the level of indentations, arising from Sertoli cells and encompassing germ cells. Finally, the present findings strongly suggest that cadherins are also involved in the spermiogenesis as germ cells, when male gamete differentiation starts, are intensively stained, while, when spermiation is completed, the spermatozoa appear unlabeled.
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Affiliation(s)
- Marina Prisco
- Department of Biological Science, University of Naples Federico II, Naples, Italy.
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Li X, Amarnath D, Kato Y, Tsunoda Y. Analysis of Development-Related Gene Expression in Cloned Bovine Blastocysts with Different Developmental Potential. CLONING AND STEM CELLS 2006; 8:41-50. [PMID: 16571076 DOI: 10.1089/clo.2006.8.41] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The high incidence of abnormalities in cloned calves is a most serious problem for bovine somatic cell nuclear transfer (NT) technology. Because there is little information on the differences in mRNA expression in cloned blastocysts with donor cells of different sex and origin, we compared development-related gene expression in two types of cloned bovine blastocysts with different potentials to develop into normal calves, a female adult cumulus cell line (high potential to develop into live calves) and a male fibroblast cell line (low potential to develop into live calves) to examine the correlation between the normality of cloned calves and blastocyst mRNA expression patterns. We analyzed 12 genes involved in apoptosis, growth factor signaling, metabolism, and DNA methylation in blastocysts originating from two types of donor cells and in vitro-fertilized blastocysts using quantitative real-time polymerase chain reaction. Expression of the pro-apoptotic Bax gene and anti-apoptotic Bcl-2 and Glut-1 genes in fibroblast-derived blastocysts was significantly higher than in cumulus cell-derived and in vitro-fertilized blastocysts. The high Bcl-2 and Glut-1 gene expression suggests that some embryonic cells with damaged DNA in fibroblast-derived blastocysts are not removed, and their descendants later manifest abnormal placenta or fetus formation. Transfer of pre-selected cloned blastocysts into recipients is required, however, to determine whether the expression pattern of these apoptosis-related genes reflects differences in the potential to develop into normal calves.
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Affiliation(s)
- Xiangping Li
- Laboratory of Animal Reproduction, College of Agriculture, Kinki University, Nakamachi, Nara, Japan
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Peluso JJ. N-cadherin mediated cell contact inhibits germinal vesicle breakdown in mouse oocytes maintained in vitro. Reproduction 2006; 131:429-37. [PMID: 16514186 DOI: 10.1530/rep.1.00863] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The effect of granulosa cell contact on the ability of zona-free oocytes to undergo germinal vesicle breakdown (GVBD) was assessed using a granulosa cell co-culture system. Oocytes contacted granulosa cells in a site-specific manner such that their GV was away from the granulosa cells. Also contact with granulosa cells reduced the percentage of oocytes undergoing GVBD from about 40% to 15%. GVBD was inhibited by contact with granulosa cells but not a granulosa cell-secreted product, since oocytes cultured in the same culture, that were adjacent to the granulosa cell monolayer underwent GVBD at the same rate as controls. Similarly, media collected from granulosa cell cultures did not attenuate the rate of GVBD. The ability of granulosa cell contact to inhibit GVBD was equal to that of db-cAMP. Moreover, the ability of granulosa cells to inhibit GVBD was not mimicked by spontaneously immortalized granulosa cells. This cell specificity appeared to be related to N-cadherin, since granulosa cells and oocytes express N-cadherin and a N-cadherin antibody attenuates the effect of granulosa cell contact. The mechanism through which N-cadherin mediated cell contact maintains meiotic arrest is unknown. It is possible that homophilic N-cadherin binding between the granulosa cells and oocyte acts through a junxtacrine mechanism, which in part may lead in the activation fibroblast growth factor (FGF) receptors that are expressed by the oocyte. The involvement of FGF receptors is supported by the observations that FGF and a N-cadherin peptide known to activate FGF receptors inhibit GVBD.
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Affiliation(s)
- J J Peluso
- Cell Biology and Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
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Cowin P, Rowlands TM, Hatsell SJ. Cadherins and catenins in breast cancer. Curr Opin Cell Biol 2005; 17:499-508. [PMID: 16107313 DOI: 10.1016/j.ceb.2005.08.014] [Citation(s) in RCA: 261] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2005] [Accepted: 08/03/2005] [Indexed: 01/10/2023]
Abstract
Recent studies show that cadherins and catenins are hormonally regulated and carry out physiological roles during mammary development but have pathological effects when deregulated. E-cadherin expression is irreversibly lost in invasive lobular breast cancer (ILC). Animal models of ILC provide mechanistic insight, confirming that E-cadherin serves as both a tumor suppressor and an invasion suppressor in ILC. Ductal breast cancer involves complex, reversible, epigenetic modulation of multiple cadherins. Transcriptional regulators of E-cadherin have been identified that induce epithelial-to-mesenchymal transitions. Catenins are lost or mislocalized in tumors lacking cadherins. However, beta-catenin signaling is upregulated by numerous pathways in >50% of breast tumors and animal models suggest its oncogenic function in breast relates to its role in mammary progenitor cell expansion.
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Affiliation(s)
- Pamela Cowin
- Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA.
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