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R. B. Hufnagel, M. Quinn, N. L. Brown; Opposing Roles for Atoh7 and Ascl1 in Cell Cycle Exit and Fate Specification of Retinal Progenitors. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1309.
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Retinal neurons and glia differentiate in a stereotypical birth order in mice, with retinal ganglion cells (RGCs) born first and bipolar neurons and Müller glia last. The bHLH transcription factors Atoh7 and Ascl1 are required for normal RGC and bipolar development, respectively. Atoh7 expression begins at the initiation of neurogenesis, three days prior to Ascl1 onset. We have misexpressed Ascl1 precociously in the Atoh7-lineage to test the potency of the earliest retinal progenitors.
Atoh7Ascl1 mice were generated by targeted replacement of Atoh7 by Ascl1 coupled to an IRES-DsRed2 reporter cassette. Embryonic, postnatal, and adult mouse eyes were harvested from timed pregnancies for histology and immunohistochemistry. BrdU pulse-labeling and birthdating experiments were performed at embryonic or neonatal ages, and eyes collected at different ages for analysis.
Atoh7Ascl1/Ascl1 mice have essentially no RGCs, like Atoh7 mutants, but have increased bipolar neurons and decreased Müller glia. At the initiation of retinal neurogenesis, Ascl1-misexpressing cells fail to differentiate and remain inappropriately mitotically active. Additionally, birthdating studies indicate that the onset of bipolar neurogenesis is unaffected in Atoh7Ascl1/Ascl1 retinae.
Ascl1 cannot compensate for Atoh7 in specifying the RGC fate. However, Ascl1 misexpression redirects early progenitors to adopt a bipolar fate. Embryonic Atoh7-expressing retinal cells are predominantly postmitotic. Substitution of Atoh7 for Ascl1 prolongs mitotic activity, which contributes to early progenitor differentiation postnatally as bipolar neurons.
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