Identification of neural crest and glial enhancers at the mouse Sox10 locus through transgenesis in zebrafish.
Sox10 is a dynamically regulated transcription factor gene that is essential for the development of neural crest-derived and oligodendroglial populations. Developmental genes often require multiple regulatory sequences that integrate discrete and overlapping functions to coordinate their expression. To identify Sox10 cis-regulatory elements, we integrated multiple model systems, including cell-based screens and transposon-mediated transgensis in zebrafish, to scrutinize mammalian conserved, noncoding genomic segments at the mouse Sox10 locus. We demonstrate that eight of 11 Sox10 genomic elements direct reporter gene expression in transgenic zebrafish similar to patterns observed in transgenic mice, despite an absence of observable sequence conservation between mice and zebrafish. Multiple segments direct expression in overlapping populations of neural crest derivatives and glial cells, ranging from pan-Sox10 and pan-neural crest regulatory control to the modulation of expression in subpopulations of Sox10-expressing cells, including developing melanocytes and Schwann cells. Several sequences demonstrate overlapping spatial control, yet direct expression in incompletely overlapping developmental intervals. We were able to partially explain neural crest expression patterns by the presence of head to head SoxE family binding sites within two of the elements. Moreover, we were able to use this transcription factor binding site signature to identify the corresponding zebrafish enhancers in the absence of overall sequence homology. We demonstrate the utility of zebrafish transgenesis as a high-fidelity surrogate in the dissection of mammalian gene regulation, especially those with dynamically controlled developmental expression.
Antonellis
Anthony
A
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Huynh
Jimmy L
JL
Lee-Lin
Shih-Queen
SQ
Vinton
Ryan M
RM
Renaud
Gabriel
G
Loftus
Stacie K
SK
Elliot
Gene
G
Wolfsberg
Tyra G
TG
Green
Eric D
ED
McCallion
Andrew S
AS
Pavan
William J
WJ
D000818:Animals; D030801:Animals, Genetically Modified; D001665:Binding Sites; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D018014:Gene Transfer Techniques; D016678:Genome; D006609:High Mobility Group Proteins / Q000235:genetics* / Q000378:metabolism; D008544:Melanocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D009432:Neural Crest / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D055757:SOXE Transcription Factors; D012583:Schwann Cells / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D014157:Transcription Factors
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