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F. C. Chiodini, V, D. Skowronska-Krawczyk, A. Kundzewicz, C. Alliod, L. Matter-Sadzinski, J.-M. Matter; Atoh7-Mediated Regulation of the Hes5 Genes During Retina Ontogenesis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4006.
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© ARVO (1962-2015); The Authors (2016-present)
The Atonal Homolog 5 (ATH5/Atoh7) protein plays a critical role in the ontogenesis of vertebrate retina. We have identified targets of Atoh7 along the pathway leading to the conversion of proliferating progenitors into newborn Retinal Ganglion Cells (RGCs). We show how Atoh7-mediated cross-regulations between the chicken homolog of enhancer of split 5.1, 5.2, 5.3 (HES5.1, HES5.2, HES5.3) may coordinate neuronal specification and cell cycle exit during retina ontogenesis.
We have performed ChIP-chip screens at two consecutive developmental time periods: embryonic day 3.5 (HH22-23) and embryonic day 6 (HH29-30), covering the stages of retinal progenitor proliferation, RGC specification and early neuronal differentiation. Promoter/enhancer properties of Atoh7-bound sequences were analyzed in chick retinas. To define the status of cells expressing these targets, interkinetic nuclear migration (INM) was monitored by confocal time-lapse imaging.
We identified HES5.1, HES5.2 and HES5.3 as direct targets of Atoh7. HES5 are essential Notch effectors in regulation of neuronal differentiation and are known to counteract neurogenesis in mammals and birds. The positive regulation of these genes by Atoh7 raises the question of the role they might play during retina ontogenesis. HES5.2, HES5.3 and Atoh7 were co-expressed in a subset of proliferating progenitors. Before they exited the cell cycle, these cells paused in S/G2. During this period Atoh7 was coordinating a switch between HES5.3 and HES5.1 and it activated β3 nAChR - i.e., an early marker of RGC differentiation and a target of Atoh7. Then, cells went through their last mitosis and, while residing along the apical surface, newborn HES5.1-expressing RGCs were extending axons towards the basal surface.
Atoh7 by mediating cross-regulations between the HES5 genes coordinates consecutive events leading a subset of uncommitted progenitors to enter the RGC lineage and to become newborn RGCs.
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