A Positive Feedback Loop between ATOH7 and a Notch Effector Regulates Cell-Cycle Progression and Neurogenesis in the Retina

Abstract

The HES proteins are known Notch effectors and have long been recognized as important in inhibiting neuronal differentiation. However, the roles that they play in the specification of neuronal fate remain largely unknown. Here, we show that in the differentiating retinal epithelium, the proneural protein ATOH7 (ATH5) is required for the activation of the transcription of the Hes5.3 gene before the penultimate mitosis of progenitor cells. We further show that the HES5.3 protein slows down the cell-cycle progression of Atoh7-expressing cells, thereby establishing conditions for Atoh7 to reach a high level of expression in S phase and induce neuronal differentiation prior to the ultimate mitosis. Our study uncovers how a proneural protein recruits a protein known to be a component of the Notch signaling pathway in order to regulate the transition between an initial phase of selection among uncommitted progenitors and a later phase committing the selected progenitors to neuronal differentiation.

Delayed neurogenesis with respect to eye growth shapes the pigeon retina for high visual acuity

“…By contrast, expression of the Hes5 genes was delayed in pigeon ( Fig. S4B-D), consistent with the fact that they are activated by ATOH7 (Chiodini et al, 2013). The interplay between ATOH7 and HES5.3 is indeed required for cells to upregulate Atoh7 and to enter the RGC lineage.…”

“…The interplay between ATOH7 and HES5.3 is indeed required for cells to upregulate Atoh7 and to enter the RGC lineage. Despite the fact that Hes5.3 expression is detected in the whole subset of Atoh7-expressing progenitor cells, only 25-30% of them upregulate Atoh7 and enter this lineage in chick between E3 and E5 (Chiodini et al, 2013;Matter-Sadzinski et al, 2005). This low efficiency of RGC production at early stages is attributed to the negative effect of HES1 on Atoh7 cis-acting regulatory elements (Hernandez et al, 2007), hence keeping transcription of the Atoh7 gene at a low level in progenitor cells.…”

“…5B). Atoh7-RFP identifies cells expressing Atoh7 at high level and that enter the RGC lineage (Chiodini et al, 2013). We calculated the fractions of Atoh7-expressing cells, and we estimated that in pigeon three times as many cells entered the RGC lineage during this 24-h period (∼1.26×10 6 versus ∼0.43×10 6 cells/retina in pigeon versus chick; Fig.…”

“…Sustained expression of ATOH7 is required during the last cell cycle for cells to enter the RGC lineage. In chick, efficient NGN2-mediated activation of Atoh7 transcription, Atoh7 autostimulation and HES5.3-mediated lengthening of the cell cycle increase the proportion of cells that enter this lineage (Chiodini et al, 2013;Skowronska-Krawczyk et al, 2009). However, this still does not result in numbers of RGCs as high as in the macula and fovea (Fig.…”

“…S3C; e.g. Stmn2, Chrnb3, Ptn) (Chiodini et al, 2013;Skowronska-Krawczyk et al, 2009), indicates that neuronal differentiation is delayed in pigeon. Deferred expression of TFs that exert control over photoreceptor, amacrine, horizontal and bipolar cell specification (Fig.…”