Mutations in key transcription factors SOX2 and P63 were linked with developmental defectsand postnatal abnormalities such as corneal opacification, neovascularization, and blindness. Thelatter phenotypes suggest that SOX2 and P63 may be involved in corneal epithelial regeneration.Although P63 has been shown to be a key regulator of limbal stem cells, the expression patternand function of SOX2 in the adult cornea remained unclear. Here, we show that SOX2 regulatesP63 to control corneal epithelial stem/progenitor cell function. SOX2 and P63 were co-expressedin the stem/progenitor cell compartments of the murine cornea in vivo and in undifferentiatedhuman limbal epithelial stem/progenitor cells in vitro. In line, a new consensus site that allowsSOX2-mediated regulation of P63 enhancer was identified while repression of SOX2 reduced P63expression, suggesting that SOX2 is upstream to P63. Importantly, knockdown of SOX2 signifi-cantly attenuated cell proliferation, long-term colony-forming potential of stem/progenitor cells,and induced robust cell differentiation. However, this effect was reverted by forced expression ofP63, suggesting that SOX2 acts, at least in part, through P63. Finally, miR-450b was identified as adirect repressor of SOX2 that was required for SOX2/P63 downregulation and cell differentiation.Altogether, we propose that SOX2/P63 pathway is an essential regulator of corneal stem/progeni-tor cells while mutations in SOX2 or P63 may disrupt epithelial regeneration, leading to loss ofcorneal transparency and blindness.
展开▼