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Genomic code for Sox10 activation reveals a key regulatory enhancer for cranial neural crest

Betancur, Paola and Bronner-Fraser, Marianne and Sauka-Spengler, Tatjana (2010) Genomic code for Sox10 activation reveals a key regulatory enhancer for cranial neural crest. Proceedings of the National Academy of Sciences of the United States of America, 107 (8). pp. 3570-3575. ISSN 0027-8424. PMCID PMC2840498. https://resolver.caltech.edu/CaltechAUTHORS:20100406-105200553

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Abstract

The neural crest is a multipotent, stem cell-like population that migrates extensively in the embryo and forms a wide array of derivatives, ranging from neurons to melanocytes and cartilage. Analyses of the gene regulatory network driving neural crest development revealed Sox10 as one of the earliest neural crest-specifying genes, cell-autonomously driving delamination and directly regulating numerous downstream effectors and differentiation gene batteries. In search of direct inputs to the neural crest specifier module, we dissected the chick Sox10 genomic region and isolated two downstream regulatory regions with distinct spatiotemporal activity. A unique element, Sox10E2 represents the earliest-acting neural crest cis-regulatory element, critical for initiating Sox10 expression in newly formed cranial, but not vagal and trunk neural crest. A second element, Sox10E1, acts in later migrating vagal and trunk crest cells. Deep characterization of Sox10E2 reveals Sox9, Ets1, and cMyb as direct inputs mediating enhancer activity. ChIP, DNA-pull down, and gel-shift assays demonstrate their direct binding to the Sox10E2 enhancer in vivo, whereas mutation of their corresponding binding sites, or inactivation of the three upstream regulators, abolishes both reporter and endogenous Sox10 expression. Using cis-regulatory analysis as a tool, our study makes critical connections within the neural crest gene regulatory network, thus being unique in establishing a direct link of upstream effectors to a key neural crest specifier.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.0906596107 DOIArticle
http://www.pnas.org/content/107/8/3570PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840498/PubMed CentralArticle
http://www.pnas.org/cgi/content/full/0906596107/DCSupplementalPublisherSupporting Information
ORCID:
AuthorORCID
Bronner-Fraser, Marianne0000-0003-4274-1862
Sauka-Spengler, Tatjana0000-0001-9289-0263
Additional Information:© 2010 by the National Academy of Sciences. Edited by Eric H. Davidson, California Institute of Technology, Pasadena, CA, and approved December 8, 2009 (received for review June 16, 2009). We thank Dr. S. Fraser for critical reading of the manuscript, M. Jones for excellent technical assistance, Drs. H. Kondoh for ptk-EGFP reporter construct, Y.-C. Cheng for full-length Sox9 and Sox10 constructs, M. Dvorak for gift of cMyb antibody, M. Wegner for Sox9 antibody, P. Strobl for help with H3K36me3 ChIP, G. Hernandez and D. Meulemans Medeiros for helpful discussions, and M. Barembaum and M. Morales-Del Real for help with in situs. This work was supported by a California Institute of Regenerative Medicine Fellowship (to T.S.S.) and Grants NS36585 and P01-HD037105 (to M.B.-F.). Author contributions: P.B., M.B.-F., and T.S.-S. designed research; P.B. and T.S.-S. performed research; T.S.-S. contributed new reagents/analytic tools; P.B. and T.S.-S. analyzed data; and P.B., M.B.-F., and T.S.-S. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. This article contains supporting information online at www.pnas.org/cgi/content/full/0906596107/DCSupplemental.
Funders:
Funding AgencyGrant Number
California Institute for Regenerative Medicine (CIRM)UNSPECIFIED
NIHP01-HD037105
NIHNS36585
Issue or Number:8
PubMed Central ID:PMC2840498
Record Number:CaltechAUTHORS:20100406-105200553
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20100406-105200553
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:17868
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:14 Apr 2010 19:29
Last Modified:09 Mar 2020 13:19

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