Sox2 is required for olfactory pit formation and olfactory neurogenesis through BMP restriction and <i>Hes5</i> upregulation

Abstract

The transcription factor Sox2 is necessary to maintain pluripotency of embryonic stem cells, and to regulate neural development. Neurogenesis in the vertebrate olfactory epithelium persists from embryonic stages through adulthood. The role <i>Sox2</i> plays for the development of the olfactory epithelium and neurogenesis within has, however, not been determined. Here, by analysing <i>Sox2</i> conditional knockout mouse embryos and chick embryos deprived of <i>Sox2</i> in the olfactory epithelium using CRISPR-Cas9, we show that Sox2 activity is crucial for the induction of the neural progenitor gene <i>Hes5</i> and for subsequent differentiation of the neuronal lineage. Our results also suggest that Sox2 activity promotes the neurogenic domain in the nasal epithelium by restricting <i>Bmp4</i> expression. The <i>Sox2-</i>deficient olfactory epithelium displays diminished cell cycle progression and proliferation, a dramatic increase in apoptosis and finally olfactory pit atrophy. Moreover, chromatin immunoprecipitation data show that Sox2 directly binds to the <i>Hes5</i> promoter in both the PNS and CNS. Taken together, our results indicate that Sox2 is essential to establish, maintain and expand the neuronal progenitor pool by suppressing <i>Bmp4</i> and upregulating <i>Hes5</i> expression.