Conserved regulatory sequences in<i>Atoh7</i>mediate non-conserved regulatory responses in retina ontogenesis

Skowronska‐Krawczyk, Dorota; Chiodini, Florence; Ebeling, Martin; Alliod, Christine; Kundzewicz, Adam; Castro, Diogo S.; Ballivet, Marc; Guillemot, François; Matter-Sadzinski, Lidia; Matter, Jean‐Marc

doi:10.1242/dev.033449

Cited by 38 publications

(45 citation statements)

References 60 publications

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“…In single-cell gene expression-profiling experiments, roughly similar fractions of progenitors expressed Ascl1, Ngn2 or both factors (Trimarchi et al, 2008 (Ohsawa and Kageyama, 2008); each factor (or combination of factors) is instructive for a specific cell fate. This seems unlikely for Ascl1 and Ngn2, as mice deficient in these transcription factors are able to generate all of the seven principal retinal cell types (Akagi et al, 2004;Hufnagel et al, 2010;Skowronska-Krawczyk et al, 2009;Tomita et al, 2000). Alternatively, these factors could bias progenitors towards neural fates.…”

Section: Progenitor Heterogeneity Correlates With Different Fate Outcmentioning

confidence: 99%

Ascl1 expression defines a subpopulation of lineage-restricted progenitors in the mammalian retina

et al. 2011

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The mechanisms of cell fate diversification in the retina are not fully understood. The seven principal cell types of the neural retina derive from a population of multipotent progenitors during development. These progenitors give rise to multiple cell types concurrently, suggesting that progenitors are a heterogeneous population. It is thought that differences in progenitor gene expression are responsible for differences in progenitor competence (i.e. potential) and, subsequently, fate diversification. To elucidate further the mechanisms of fate diversification, we assayed the expression of three transcription factors made by retinal progenitors: Ascl1 (Mash1), Ngn2 (Neurog2) and Olig2. We observed that progenitors were heterogeneous, expressing every possible combination of these transcription factors. To determine whether this progenitor heterogeneity correlated with different cell fate outcomes, we conducted Ascl1- and Ngn2-inducible expression fate mapping using the CreER™/LoxP system. We found that these two factors gave rise to markedly different distributions of cells. The Ngn2 lineage comprised all cell types, but retinal ganglion cells (RGCs) were exceedingly rare in the Ascl1 lineage. We next determined whether Ascl1 prevented RGC development. Ascl1-null mice had normal numbers of RGCs and, interestingly, we observed that a subset of Ascl1+ cells could give rise to cells expressing Math5 (Atoh7), a transcription factor required for RGC competence. Our results link progenitor heterogeneity to different fate outcomes. We show that Ascl1 expression defines a competence-restricted progenitor lineage in the retina, providing a new mechanism to explain fate diversification.

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Section: Progenitor Heterogeneity Correlates With Different Fate Outcmentioning

confidence: 99%

Ascl1 expression defines a subpopulation of lineage-restricted progenitors in the mammalian retina

et al. 2011

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“…However, whereas the majority of the ATOH7-expressing cells enter the RGC lineage in the chick, only a few percent produce RGCs in the mouse (Prasov and Glaser, 2012;Skowronska-Krawczyk et al, 2009;Yang et al, 2003). Sustained expression of ATOH7 is required during the last cell cycle for cells to enter the RGC lineage.…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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The macula and fovea located at the optical centre of the retina make primate visual perception unique among mammals. Our current understanding of retina ontogenesis is primarily based on animal models having no macula and no fovea. However, the pigeon retina and the human macula share a number of structural and functional properties that justify introducing the former as a new model system for retina development. Comparative transcriptome analysis of pigeon and chicken retinas at different embryonic stages reveals that the genetic programmes underlying cell differentiation are postponed in the pigeon until the end of the period of cell proliferation. We show that the late onset of neurogenesis has a profound effect on the developmental patterning of the pigeon retina, which is at odds with the current models of retina development. The uncoupling of tissue growth and neurogenesis is shown to result from the fact that the pigeon retinal epithelium is inhibitory to cell differentiation. The sum of these developmental features allows the pigeon to build a retina that displays the structural and functional traits typical of primate macula and fovea.

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“…Lineage tracing studies demonstrated that RPCs expressing either Atoh7 and/or Neurog2 give rise to all seven major cell classes (Ma and Wang, 2006;Feng et al, 2010;Brzezinski et al, 2012). Importantly, Neurog2 directly activates Atoh7 transcription by binding to an evolutionarily conserved E box in the primary Atoh7 retinal enhancer, and in Neurog2 mutants, Atoh7 expression is delayed along with advancement of neurogenesis (Skowronska-Krawczyk et al, 2009;Hufnagel et al, 2010). The individual requirements of Atoh7 and Neurog2 account for those of the Drosophila orthologue, atonal (ato), in the fly eye (Jarman et al, 1993(Jarman et al, , 1994(Jarman et al, , 1995Brown et al, 2001;Wang et al, 2001;Hufnagel et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Notch signaling differentially regulatesAtoh7andNeurog2in the distal mouse retina

2014

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Notch signaling regulates basic helix-loop-helix (bHLH) factors as an evolutionarily conserved module, but the tissue-specific mechanisms are incompletely elucidated. In the mouse retina, bHLH genes Atoh7 and Neurog2 have distinct functions, with Atoh7 regulating retinal competence and Neurog2 required for progression of neurogenesis. These transcription factors are extensively co-expressed, suggesting similar regulation. We directly compared Atoh7 and Neurog2 regulation at the earliest stages of retinal neurogenesis in a broad spectrum of Notch pathway mutants. Notch1 and Rbpj normally block Atoh7 and Neurog2 expression. However, the combined activities of Notch1, Notch3 and Rbpj regulate Neurog2 patterning in the distal retina. Downstream of the Notch complex, we found the Hes1 repressor mediates Atoh7 suppression, but Hes1, Hes3 and Hes5 do not regulate Neurog2 expression. We also tested Notch-mediated regulation of Jag1 and Pax6 in the distal retina, to establish the appropriate context for Neurog2 patterning. We found that Notch1;Notch3 and Rbpj block co-expression of Jag1 and Neurog2, while specifically stimulating Pax6 within an adjacent domain. Our data suggest that Notch signaling controls the overall tempo of retinogenesis, by integrating cell fate specification, the wave of neurogenesis and the developmental status of cells ahead of this wave.

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Conserved regulatory sequences inAtoh7mediate non-conserved regulatory responses in retina ontogenesis

Cited by 38 publications

References 60 publications

Ascl1 expression defines a subpopulation of lineage-restricted progenitors in the mammalian retina

Ascl1 expression defines a subpopulation of lineage-restricted progenitors in the mammalian retina

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

Notch signaling differentially regulatesAtoh7andNeurog2in the distal mouse retina

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