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Huang T, Hou Y, Wang X, et al. Direct Interaction of Sox10 With Cadherin-19 Mediates Early Sacral Neural Crest Cell Migration: Implications for Enteric Nervous System Development Defects. Gastroenterology. 2021;162(1):179-192.e11doi: 10.1053/j.gastro.2021.08.029.
Huang, T., Hou, Y., Wang, X., Wang, L., Yi, C., Wang, C., Sun, X., Tam, P. K. H., Ngai, S. M., Sham, M. H., Burns, A. J., & Chan, W. Y. (2022). Direct Interaction of Sox10 With Cadherin-19 Mediates Early Sacral Neural Crest Cell Migration: Implications for Enteric Nervous System Development Defects. Gastroenterology, 162(1), 179-192.e11. https://doi.org/10.1053/j.gastro.2021.08.029
Huang, Taida, et al. "Direct Interaction of Sox10 With Cadherin-19 Mediates Early Sacral Neural Crest Cell Migration: Implications for Enteric Nervous System Development Defects." Gastroenterology vol. 162,1 (2022): 179-192.e11. doi: https://doi.org/10.1053/j.gastro.2021.08.029
Huang T, Hou Y, Wang X, Wang L, Yi C, Wang C, Sun X, Tam PKH, Ngai SM, Sham MH, Burns AJ, Chan WY. Direct Interaction of Sox10 With Cadherin-19 Mediates Early Sacral Neural Crest Cell Migration: Implications for Enteric Nervous System Development Defects. Gastroenterology. 2022 Jan;162(1):179-192.e11. doi: 10.1053/j.gastro.2021.08.029. Epub 2021 Aug 21. PMID: 34425092.
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Gastroenterology. 2022 Jan;162(1):179-192.e11. doi: 10.1053/j.gastro.2021.08.029. Epub 2021 Aug 21.

Direct Interaction of Sox10 With Cadherin-19 Mediates Early Sacral Neural Crest Cell Migration: Implications for Enteric Nervous System Development Defects.

Gastroenterology

Taida Huang, Yonghui Hou, Xia Wang, Liang Wang, Chenju Yi, Cuifang Wang, Xiaoyun Sun, Paul K H Tam, Sai Ming Ngai, Mai Har Sham, Alan J Burns, Wood Yee Chan

Affiliations

  1. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
  2. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Department of Orthopedic Surgery, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
  3. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Department of Anatomy, Histology & Developmental Biology, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen, China.
  4. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  5. Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
  6. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; College of Oceanology and Food Sciences, Quanzhou Normal University, Quanzhou, China.
  7. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
  8. Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Dr. Li Dak Sum Research Centre, The University of Hong Kong, Hong Kong, China; Faculty of Medicine, Macau University of Science and Technology, Macau, China.
  9. School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, China.
  10. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
  11. Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Gastrointestinal Drug Discovery Unit, Takeda Pharmaceuticals International, Cambridge, Massachusetts. Electronic address: [email protected].
  12. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: [email protected].

PMID: 34425092 DOI: 10.1053/j.gastro.2021.08.029

Abstract

BACKGROUND AND AIMS: The enteric nervous system, which regulates many gastrointestinal functions, is derived from neural crest cells (NCCs). Defective NCC migration during embryonic development may lead to enteric neuropathies such as Hirschsprung's disease (hindgut aganglionosis). Sox10 is known to be essential for cell migration but downstream molecular events regulating early NCC migration have not been fully elucidated. This study aimed to determine how Sox10 regulates migration of sacral NCCs toward the hindgut using Dominant megacolon mice, an animal model of Hirschsprung's disease with a Sox10 mutation.

METHODS: We used the following: time-lapse live cell imaging to determine the migration defects of mutant sacral NCCs; genome-wide microarrays, site-directed mutagenesis, and whole embryo culture to identify Sox10 targets; and liquid chromatography and tandem mass spectrometry to ascertain downstream effectors of Sox10.

RESULTS: Sacral NCCs exhibited retarded migration to the distal hindgut in Sox10-null embryos with simultaneous down-regulated expression of cadherin-19 (Cdh19). Sox10 was found to bind directly to the Cdh19 promoter. Cdh19 knockdown resulted in retarded sacral NCC migration in vitro and ex vivo, whereas re-expression of Cdh19 partially rescued the retarded migration of mutant sacral NCCs in vitro. Cdh19 formed cadherin-catenin complexes, which then bound to filamentous actin of the cytoskeleton during cell migration.

CONCLUSIONS: Cdh19 is a direct target of Sox10 during early sacral NCC migration toward the hindgut and forms cadherin-catenin complexes which interact with the cytoskeleton in migrating cells. Elucidation of this novel molecular pathway helps to provide insights into the pathogenesis of enteric nervous system developmental defects.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: Cadherin-19; Hirschsprung’s Disease; Migration; Sacral Neural Crest Cells; Sox10 Target

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