Sox2 interacts with Atoh1 and Huwe1 loci to regulate Atoh1 transcription and stability during hair cell differentiation

Stem cell pluripotency gene Sox2 stimulates expression of proneural
basic-helix-loop-helix transcription factor Atoh1. Sox2 is necessary for
the development of cochlear hair cells and binds to the Atoh1 3’ enhancer
to stimulate Atoh1 expression. We show here that Sox2 deletion in late
embryogenesis results in the formation of extra hair cells, in contrast to
the absence of hair cell development obtained after Sox2 knockout early in
gestation. Sox2 overexpression decreased the level of Atoh1 protein
despite an increase in Atoh1 mRNA. Sox2 upregulated E3 ubiquitin ligase,
Huwe1, by direct binding to the Huwe1 gene. By upregulating its cognate E3
ligase, Sox2 disrupts the positive feedback loop through which Atoh1
protein increases the expression of Atoh1. We conclude that Sox2 initiates
expression, while also limiting continued activity of bHLH transcription
factor, Atoh1, and this inhibition represents a new mechanism for
regulating the activity of this powerful initiator of hair cell
development.