Regulators of gene expression in Enteric Neural Crest Cells are putative Hirschsprung disease genes

Duco Schriemer, Yunia Sribudiani, Arne IJpma, Dipa Natarajan, Katherine C. MacKenzie, Marco Metzger, Ellen Binder, Alan J. Burns, Nikhil Thapar, Robert M. W. Hofstra, Bart J. L. Eggen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The enteric nervous system (ENS) is required for peristalsis of the gut and is derived from Enteric Neural Crest Cells (ENCCs). During ENS development, the RET receptor tyrosine kinase plays a critical role in the proliferation and survival of ENCCs, their migration along the developing gut, and differentiation into enteric neurons. Mutations in RET and its ligand GDNF cause Hirschsprung disease (HSCR), a complex genetic disorder in which ENCCs fail to colonize variable lengths of the distal bowel. To identify key regulators of ENCCs and the pathways underlying RET signaling, gene expression profiles of untreated and GDNF-treated ENCCs from E14.5 mouse embryos were generated. ENCCs express genes that are involved in both early and late neuronal development, whereas GDNF treatment induced neuronal maturation. Predicted regulators of gene expression in ENCCs include the known HSCR genes Ret and Sox10, as well as Bdnf, App and Mapk10. The regulatory overlap and functional interactions between these genes were used to construct a regulatory network that is underlying ENS development and connects to known HSCR genes. In addition, the adenosine receptor Ala (Adora2a) and neuropeptide Y receptor Y2 (Npy2r) were identified as possible regulators of terminal neuronal differentiation in GDNF-treated ENCCs. The human orthologue of Npy2r maps to the HSCR susceptibility locus 4q31.3-q32.3, suggesting a role for NPY2R both in ENS development and in HSCR. (C) 2016 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)255-265
Number of pages11
JournalDevelopmental Biology
Volume416
Issue number1
DOIs
Publication statusPublished - 1-Aug-2016

Keywords

  • Hirschsprung disease
  • Enteric nervous system
  • Transcriptome
  • Upstream Regulators
  • AMYLOID PRECURSOR PROTEIN
  • MICE LACKING GDNF
  • RECEPTOR TYROSINE KINASE
  • NERVOUS-SYSTEM
  • MOUSE MODEL
  • NEUROTROPHIC FACTOR
  • NEUROPEPTIDE-Y
  • NEURONAL DIFFERENTIATION
  • RET PROTOONCOGENE
  • IN-VITRO

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