Abstract
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.
Highlights
The neural crest is a transient migratory population of cells that arise at the dorsal aspect of the neural tube as it closes and that give rise to myriad structures including, but not limited to, melanocytes, enteric nervous system (ENS), and myelinating Schwann cells [1]
While neither Sox10-MCS1 nor Sox10-MCS1B displayed enhancer activity, Sox10-MCS1C directed reporter gene expression in both melanocytes and Schwann cells (Figure 1F). These data suggest that Sox10-MCS1C may represent a proximal Sox10 enhancer element
We identified the subset of these consensus sequences that have a conservation profile consistent with Sox10-MCS4 and Sox10MCS7 and that reside within intronic regions of genes expressed in melanocytes
Summary
The neural crest is a transient migratory population of cells that arise at the dorsal aspect of the neural tube as it closes and that give rise to myriad structures including, but not limited to, melanocytes, enteric nervous system (ENS), and myelinating Schwann cells [1]. SOX10 (SRY-box containing gene 10) encodes a critical transcription factor in neural crest development [2,3]. All neural crest cells express SOX10 upon emigration throughout the early stages of their respective journeys. SOX10 expression is maintained in melanocytes (mouse) and Schwann cells (mouse and zebrafish) [2,3,4,5,6,7,8]. Occurring and induced mutations in animal models and spontaneous mutations in the human population exemplify the developmental requirement for Sox during development.
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