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The enteric nervous system (ENS) predominantly originates from vagal neural crest (VNC) cells that emerge from the caudal hindbrain, invade the foregut and populate the gastrointestinal tract. However, the gene regulatory network (GRN) orchestrating the early specification of VNC remains unknown. Using an EdnrB enhancer, we generated a comprehensive temporal map of the chromatin and transcriptional landscape of VNC in the avian model, revealing three VNC cell clusters (neural, neurogenic and mesenchymal), each predetermined epigenetically prior to neural tube delamination. We identify and functionally validate regulatory cores (Sox10/Tfap2B/SoxB/Hbox) mediating each programme and elucidate their combinatorial activities with other spatiotemporally specific transcription factors (bHLH/NR). Our global deconstruction of the VNC-GRN in vivo sheds light on critical early regulatory mechanisms that may influence the divergent neural phenotypes in enteric neuropathies.

Original publication

DOI

10.1038/s41556-019-0428-9

Type

Journal article

Journal

Nat Cell Biol

Publication Date

12/2019

Volume

21

Pages

1504 - 1517

Keywords

Animals, Cell Lineage, Chickens, Chromatin, Enteric Nervous System, Epigenesis, Genetic, Gene Regulatory Networks, Mesenchymal Stem Cells, Neural Crest, Neurogenesis, Neurons, Transcription Factors, Transcription, Genetic, Vagus Nerve