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E. M. Levine, S. Yun; The Lim-Homeodomain Gene Lhx2 Is Required for the Self-Renewal of Retinal Progenitor Cells (RPCs) During Development. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1231.
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Lhx2 is a key regulator of early eye development. Lhx2 knockout mice have anophthalmia and we recently showed that Lhx2 acts as a molecular node linking eye field specification with lens formation and the patterning of the optic neuroepithelium. Lhx2 is also expressed in the retina during the subsequent stages of eye development, but the anophthalmic phenotype precludes studying its later requirements. We therefore generated mice carrying an Lhx2 conditional allele (Lhx2flox) with the Pax6 alpha enhancer cre driver (alpha-cre) and a tamoxifen (TM) regulated cre driver active in RPCs (Hes1creERT2) to determine the requirements of Lhx2 during retinal histogenesis.
Lhx2flox; alpha-cre and Lhx2flox; Hes1creERT2 embryos (TM exposure starting at E10.5) were harvested at several developmental timepoints. Phenotypes were examined by immunohistochemistry and in-situ hybridization.
Lhx2 is expressed in the majority of RPCs during retinal histogenesis. Loss of Lhx2 resulted in an extensive depletion of RPCs due to a failure to remain in the cell cycle regardless of the cre driver utilized or the time of Lhx2 inactivation. Interestingly, the exited RPCs adopted fates that were characteristic of the stage when Lhx2 was eliminated and this occurred at the expense of later generated cell types.
Our results suggest that Lhx2 regulates histogenesis by preventing RPCs from exiting the cell cycle and from acquiring a state that predisposes or biases them toward the cell fates being generated at that time. By acting in this manner, Lhx2 maintains the RPC pool by actively promoting the self-renewal of an otherwise uncommitted state.
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