Multiple Roles of Ret Signalling During Enteric Neurogenesis

Dipa Natarajan, Conor McCann, Justine Dattani, Vassilis Pachnis, Nikhil Thapar

Research output: Contribution to journalArticlepeer-review

3 Citations (SciVal)

Abstract

The majority of the enteric nervous system is formed by vagal neural crest cells which enter the foregut and migrate rostrocaudally to colonise the entire length of the gastrointestinal tract. Absence of enteric ganglia from the distal colon are the hallmark of Hirschsprung disease, a congenital disorder characterised by severe intestinal dysmotility. Mutations in the receptor tyrosine kinase RET have been identified in approximately 50% of familial cases of Hirschsprung disease but the cellular processes misregulated in this condition remain unclear. By lineage tracing neural crest cells in mice homozygous for a knock-in allele of Ret (Ret51/51), we demonstrate that normal activity of this receptor is required in vivo for the migration of enteric nervous system progenitors throughout the gut. In mutant mice, progenitors of enteric neurons fail to colonise the distal colon, indicating that failure of colonisation of the distal intestine is a major contributing factor for the pathogenesis of Hirschsprung disease. Enteric nervous system progenitors in the ganglionic proximal guts of mutant mice are also characterised by reduced proliferation and differentiation. These findings suggest that the functional abnormalities in Hirschsprung disease result from a combination of colonic aganglionosis and deficits in neuronal circuitry of more proximal gut segments. The reduced neurogenesis in the gut of Ret51/51 mutants was reproduced in the multilineage enteric nervous system progenitors isolated from these animals. Correction of the molecular defects of such progenitors fully restored their neurogenic potential in culture. These observations enhance our understanding of the pathogenesis of Hirschsprung disease and highlight potential approaches for its treatment.

Original languageEnglish
Article number832317
JournalFrontiers in Molecular Neuroscience
Volume15
DOIs
Publication statusPublished - 27 May 2022
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the UK Medical Research Council and the Francis Crick Institute, which received its core funding from Cancer Research UK (FC001128 and FC001159), the UK Medical Research Council (FC001128 and FC001159), and the Wellcome Trust (FC001128 and FC001159). VP acknowledges additional funding from BBSRC (BB/L022974) and the Wellcome Trust (212300/Z/18/Z).

Keywords

  • colonic aganglionosis
  • ENS progenitor cells
  • enteric nervous system
  • Hirschsprung disease
  • isoforms
  • neural crest cells
  • normoganglionic gut

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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