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Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest–derived enteric neuron precursors

Nature Genetics volume 36, pages 732–737 (2004)Cite this article

Abstract

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 colon1. One of the primary genes affected in HSCR encodes the G protein–coupled endothelin receptor-B (EDNRB)2,3. 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 colon4. 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 HSCR5, in the Ednrb ENS enhancer, and mutational analyses of these sites suggested that SOX10 may have multiple roles in regulating Ednrb in the ENS.

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Figure 1: Rescue of the enteric neuron defect in Ednrb-null mice.
Figure 2: Identification of ENS-specific enhancer.
Figure 3: Partial deletion of the ENS enhancer at the endogenous Ednrb locus.
Figure 4: Interaction of SOX10 at Ednrb ENS enhancer.
Figure 5: The Ednrb ENS enhancer activity is dependent on multiple SOX10 binding sites.

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Acknowledgements

We thank J. Burch and K. Zaret for critical comments on the manuscript, the members of the laboratories of M.K.S. and K. Zaret for discussions and H. Duchow and J. Levorse for establishing the P1 transgenic founders. The Fox Chase Cancer Center Automated DNA Sequencing and Transgenic facilities, supported by US National Cancer Institute Core Grant, carried out the sequencing and transgene injections, respectively. E.M.S. is supported by grants from Foundation for Digestive Health and Nutrition Research Scholar Award, Howard Hughes Medical Institute Scholar award and US National Institutes of Health. H.O.L. is supported by the Institutional Research Training Grant from National Cancer Institute. M.K.S. is supported by grants from the PEW Scholars Program in Biomedical Sciences and US National Institute of Dental and Craniofacial Research.

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Authors and Affiliations

  1. Cellular and Developmental Biology Program, Fox Chase Cancer Center, Philadelphia, 19111, Pennsylvania, USA

    Lei Zhu, Hyung-Ok Lee & Myung K Shin

  2. Department of Molecular Biology, Princeton University, Princeton, 08544, New Jersey, USA

    ChaRandle S Jordan

  3. Division of Genetic Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, 37232-0275, Tennessee, USA

    V Ashley Cantrell & E Michelle Southard-Smith

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Correspondence to Myung K Shin.

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Zhu, L., Lee, HO., Jordan, C. et al. Spatiotemporal regulation of endothelin receptor-B by SOX10 in neural crest–derived enteric neuron precursors. Nat Genet 36, 732–737 (2004). https://doi.org/10.1038/ng1371

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