Regulators of gene expression in Enteric Neural Crest Cells are putative Hirschsprung disease genes.
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 A2a (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.
Department of Neuroscience, section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Duco
D
Schriemer
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands; Department Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
Yunia
Y
Sribudiani
Department of Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Arne
A
IJpma
Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
Dipa
D
Natarajan
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Katherine C
KC
MacKenzie
Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Fraunhofer IGB, Wuerzburg branch and Chair Tissue Engineering and Regenerative Medicine, University Hospital Wuerzburg, Wuerzburg, Germany.
Marco
M
Metzger
Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
Ellen
E
Binder
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands; Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
Alan J
AJ
Burns
Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom; Division of Neurogastroenterology and Motility, Department of Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
Nikhil
N
Thapar
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands; Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
Robert M W
RMW
Hofstra
Department of Neuroscience, section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: b.j.l.eggen@umcg.nl.
Bart J L
BJL
Eggen
D000818:Animals; D000943:Antigens, Differentiation; D002469:Cell Separation; D017615:Enteric Nervous System / Q000196:embryology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006627:Hirschsprung Disease / Q000196:embryology* / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009432:Neural Crest / Q000196:embryology*; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome
D000943:Antigens, Differentiation; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse
Enteric nervous system; Hirschsprung disease; Transcriptome; Upstream Regulators