Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest-derived enteric neuron precursors.
Hirschsprung disease (HSCR) is a multigenic, congenital disorder that affects 1 in 5,000 newborns and is characterized by the absence of neural crest-derived enteric ganglia in the colon. One of the primary genes affected in HSCR encodes the G protein-coupled endothelin receptor-B (EDNRB). The expression of Ednrb is required at a defined time period during the migration of the precursors of the enteric nervous system (ENS) into the colon. In this study, we describe a conserved spatiotemporal ENS enhancer of Ednrb. This 1-kb enhancer is activated as the ENS precursors approach the colon, and partial deletion of this enhancer at the endogenous Ednrb locus results in pigmented mice that die postnatally from megacolon. We identified binding sites for SOX10, an SRY-related transcription factor associated with HSCR, in the Ednrb ENS enhancer, and mutational analyses of these sites suggested that SOX10 may have multiple roles in regulating Ednrb in the ENS.
Zhu
Lei
L
Cellular and Developmental Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Lee
Hyung-Ok
HO
Jordan
ChaRandle S
CS
Cantrell
V Ashley
VA
Southard-Smith
E Michelle
EM
Shin
Myung K
MK
D000818:Animals; D001483:Base Sequence; D004742:Enhancer Elements, Genetic; D017615:Enteric Nervous System / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006609:High Mobility Group Proteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000502:physiology*; D017466:Receptors, Endothelin / Q000235:genetics*; D055757:SOXE Transcription Factors; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors
D006609:High Mobility Group Proteins; D009363:Neoplasm Proteins; D017466:Receptors, Endothelin; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D014157:Transcription Factors