TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human

Jean Marie Delalande, Nandor Nagy, Conor J. McCann, Dipa Natarajan, Julie E. Cooper, Gabriela Carreno, David Dora, Alison Campbell, Nicole Laurent, Polychronis Kemos, Sophie Thomas, Caroline Alby, Tania Attié-Bitach, Stanislas Lyonnet, Malcolm P. Logan, Allan M. Goldstein, Megan G. Davey, Robert M.W. Hofstra, Nikhil Thapar, Alan J. Burns*Alan J. Burns

*Corresponding author for this work

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TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning.

Original languageEnglish
Article number757646
JournalFrontiers in Molecular Neuroscience
Publication statusPublished - 23 Dec 2021

Bibliographical note

Funding Information:
This article is dedicated to the memory of RH. We would like to thank Dagan Jenkins for the IFT88 antibody, Mark Turmaine for assistance with SEM, Kevin Lee and Erwin Pauws for assistance with cartilage and bone staining as well as help with the phenotype analysis. We also thank Jan Soetaert and Bel?n Mart?n-Mart?n for help with microscopy. MD and the TALPID3 flock are supported by an Institutional Strategic Grant (ISP) to The Roslin Institute from the BBSRC. NN was supported by a Bolyai Fellowship and Hungarian Science Foundation NKFI grant (124740). CM was supported by Guts UK (Derek Butler Fellowship). We are grateful to the French Society of Fetal Pathology (SoFFoet) for participating in the study. We acknowledge the NIHR Great Ormond Street Hospital Biomedical Research Centre which supports all research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

Publisher Copyright:
Copyright © 2021 Delalande, Nagy, McCann, Natarajan, Cooper, Carreno, Dora, Campbell, Laurent, Kemos, Thomas, Alby, Attié-Bitach, Lyonnet, Logan, Goldstein, Davey, Hofstra, Thapar and Burns.


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