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Free keywords:
ENTERIC NERVOUS-SYSTEM; SHAH WS4 SYNDROME; MOUSE MODEL;
HIRSCHSPRUNG-DISEASE; REGULATORY ELEMENTS; GLIAL-CELLS; EXPRESSION;
PROTEINS; DNA; DIFFERENTIATIONBiochemistry & Molecular Biology;
Abstract:
The Sox10 transcription factor is a central regulator of vertebrate
neural crest and nervous system development. Its expression is likely
controlled by multiple enhancer elements, among them U3 (alternatively
known as MCS4). Here we analyze U3 activity to obtain deeper insights
into Sox10 function and expression in the neural crest and its
derivatives. U3 activity strongly depends on the presence of Sox10 that
regulates its own expression as commonly observed for important
developmental regulators. Sox10 bound directly as monomer to at least
three sites in U3, whereas a fourth site preferred dimers. Deletion of
these sites efficiently reduced U3 activity in transfected cells and
transgenic mice. In stimulating the U3 enhancer, Sox10 synergized with
many other transcription factors present in neural crest and developing
peripheral nervous system including Pax3, FoxD3, AP2 alpha, Krox20 and
Sox2. In case of FoxD3, synergism involved Sox10-dependent recruitment
to the U3 enhancer, while Sox10 and AP2 alpha each had to bind to the
regulatory region. Our study points to the importance of autoregulatory
activity and synergistic interactions for maintenance of Sox10
expression and functional activity of Sox10 in the neural crest
regulatory network.
