Sox2 in the differentiation of cochlear progenitor cells

Abstract

HMG domain transcription factor, Sox2, is a critical gene for the development of cochlear hair cells, the receptor cells for hearing, but this has been ascribed to expansion of the progenitors that become hair cells. Here, we show that Sox2 activated Atoh1, a transcription factor important for hair cell differentiation, through an interaction with the 3′ enhancer of Atoh1. Binding to consensus sequences in the Atoh1 enhancer was dependent on the level of Sox2, and the extent of enhancer binding correlated to the extent of activation. Atoh1 activation by Sox2 was required for embryonic hair cell development: deletion of Sox2 in an inducible mutant, even after progenitor cells were fully established, halted development of hair cells, and silencing also inhibited postnatal differentiation of hair cells induced by inhibition of γ-secretase. Sox2 is thus required in the cochlea to both expand the progenitor cells and initiate their differentiation to hair cells.

SoxNeuro and shavenbaby act cooperatively to shape denticles in the embryonic epidermis of Drosophila

“…The activity of the SoxN mammalian homolog Sox2 has been shown to depend on specific levels of the protein in embryonal carcinoma cells and embryonic stem cells (Boer et al, 2007), as well as in cochlear cells (Kempfle et al, 2016), which produce the stereocilia. Further characterization of the role of SoxN in shaping Drosophila denticles might help elucidate the forces that shape stereocilia in the human inner ear, and that go awry in some hereditary forms of deafness.…”

Atoh1 in sensory hair cell development: constraints and cofactors

“…This factor functions upstream of Atoh1 in prosensory progenitor specification (7,32,33). It is known to affect epigenetic priming in B cell development (34) and it has pioneer activity during reprogramming of fibroblasts to pluripotency (35).…”

Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea

“…Sox2 is required for hair cell specification, as prosensory cells in Sox2-deficient cochleae fail to acquire a hair cell fate (11,28). A subset of Sox2 + cells first express the prosensory transcription factor Atoh1 around E13.5 (29).…”

“…By binding to its enhancer region, Sox2 can directly activate Atoh1 (35)(36)(37)(38) and is sufficient for inducing ectopic sensory hair cells in vitro (38) and in vivo (39) in the embryonic cochlea. A subsequent reduction of Sox2 expression is also necessary for hair cell maturation, as high levels of Sox2 antagonize Atoh1 and prevent hair cell formation when overexpressed in vitro (28,35), and Sox2 activates repressors of Atoh1 (40). Because Sox2 is initially required for hair cell specification and subsequently inhibits hair cell differentiation, its relationship with hair cell formation is coined an "incoherent feed-forward loop" (41).…”