Abstract
PAX6 is a master regulatory gene involved in neuronal cell fate specification. It also plays a critical role in early eye field and subsequent limbal stem cell (LSC) determination during eye development. Defects in Pax6 cause aniridia and LSC deficiency in humans and the Sey (Small eye) phenotype in mice (Massé, K., Bhamra, S., Eason, R., Dale, N., and Jones, E. A. (2007) Nature 449, 1058-1062). However, how PAX6 specifies LSC and corneal fates during eye development is not well understood. Here, we show that PAX6 is expressed in the primitive eye cup and later in corneal tissue progenitors in early embryonic development. In contrast, p63 expression commences after that of PAX6 in ocular adnexal and skin tissue progenitors and later in LSCs. Using an in vitro feeder-free culture system, we show that PAX6 knockdown in LSCs led to up-regulation of skin epidermis-specific keratins concomitant with differentiation to a skin fate. Using gene expression analysis, we identified the involvement of Notch, Wnt, and TGF-β signaling pathways in LSC fate determination. Thus, loss of PAX6 converts LSCs to epidermal stem cells, as demonstrated by a switch in the keratin gene expression profile and by the appearance of congenital dermoid tissue.
Highlights
PAX6 is a master regulatory gene involved in eye development
It plays a critical role in early eye field and subsequent limbal stem cell (LSC) determination during eye development
We show that PAX6 is expressed in the primitive eye cup and later in corneal tissue progenitors in early embryonic development
Summary
PAX6 plays a critical role in limbal stem cell and corneal epithelial fate determination. PAX6 is a master regulatory gene involved in neuronal cell fate specification It plays a critical role in early eye field and subsequent limbal stem cell (LSC) determination during eye development. PAX6 is a key gene required for fate determination and maintenance of the corneal epithelium It is expressed in the ectoderm, which gives rise to epithelial cells of the cornea. PAX6 plays an important role in corneal fate, little is known about how PAX6 maintains LSCs and ensures their further differentiation to CECs. In this study, we explored the function of PAX6 and potential signaling pathways in corneal LSC lineage determination, and we use this information to elucidate the pathology of corneal surface disease
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