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Dicer is required for the transition from early to late progenitor state in the developing mouse retina.

ABSTRACT: MicroRNAs (miRNAs), small 19-25 nucleotide RNAs that influence gene expression through posttranscriptional regulation of mRNA translation and degradation, have recently emerged as important regulators of neural development. Using conditional knock-out of Dicer, an RNase III enzyme required for miRNA maturation, previous studies have demonstrated an essential role for miRNAs in mouse cortical, inner ear, and olfactory development. However, a previous study (Damiani et al., 2008) using a Chx10cre mouse to delete Dicer in retinal progenitors reported no defects in the retina before the second postnatal week, suggesting that miRNAs are not required for mouse retinal development. In an effort to further study the role of miRNAs during retinal development and resolve this apparent conflict, we conditionally knocked out Dicer using a different (alphaPax6cre) line of transgenic mice. In contrast to the previous study, we demonstrate an essential role for miRNAs during mouse retinal development. In the absence of Dicer in the embryonic retina, production of early generated cell types (ganglion and horizontal cells) is increased, and markers of late progenitors are not expressed. This phenotype persists into postnatal retina, in which we find the Dicer-deficient progenitors fail to generate late-born cell types such as rods and Müller glia but continue to generate ganglion cells. We further characterize the dynamic expression of miRNAs during retinal progenitor differentiation and provide a comprehensive profile of miRNAs expressed during retinal development. We conclude that Dicer is necessary for the developmental change in competence of the retinal progenitor cells.

SUBMITTER: Georgi SA

PROVIDER: S-EPMC2853880 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Dicer is required for the transition from early to late progenitor state in the developing mouse retina.

Georgi Sean A SA Reh Thomas A TA

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100301 11

MicroRNAs (miRNAs), small 19-25 nucleotide RNAs that influence gene expression through posttranscriptional regulation of mRNA translation and degradation, have recently emerged as important regulators of neural development. Using conditional knock-out of Dicer, an RNase III enzyme required for miRNA maturation, previous studies have demonstrated an essential role for miRNAs in mouse cortical, inner ear, and olfactory development. However, a previous study (Damiani et al., 2008) using a Chx10cre ...[more]

PMID: 20237275

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Project description:The oscillatory expression of Notch signaling in neural progenitors suggests that both repressors and activators of neural fate specification are expressed in the same progenitors. Since Notch1 regulates photoreceptor differentiation and contributes (together with Notch3) to ganglion cell fate specification, we hypothesized that genes encoding photoreceptor and ganglion cell fate activators would be highly expressed in Notch1 receptor-bearing (Notch1+) progenitors, directing these cells to differentiate into photoreceptors or into ganglion cells when Notch1 activity is diminished. To identify these genes, we used microarray analysis to study expression profiles of whole retinas and isolated from them Notch1+ cells at embryonic day 14 (E14) and postnatal day 0 (P0). To isolate Notch1+ cells, we utilized immunomagnetic cell separation. We also used Notch3 knockout (Notch3KO) animals to evaluate the contribution of Notch3 signaling in ganglion cell differentiation. Hierarchical clustering of 6,301 differentially expressed genes showed that Notch1+ cells grouped near the same developmental stage retina cluster. At E14, we found higher expression of repressors (Notch1, Hes5) and activators (Dll3, Atoh7, Otx2) of neuronal differentiation in Notch1+ cells compared to whole retinal cell populations. At P0, Notch1, Hes5, and Dll1 expression was significantly higher in Notch1+ cells than in whole retinas. Otx2 expression was more than thirty times higher than Atoh7 expression in Notch1+ cells at P0. We also observed that retinas of wild type animals had only 14% (P < 0.05) more ganglion cells compared to Notch3KO mice. Since this number is relatively small and Notch1 has been shown to contribute to ganglion cell fate specification, we suggested that Notch1 signaling may play a more significant role in RGC development than the Notch3 signaling cascade. Finally, our findings suggest that Notch1+ progenitors--since they heavily express both pro-ganglion cell (Atoh7) and pro-photoreceptor cell (Otx2) activators--can differentiate into either ganglion cells or photoreceptors.

Project description:BackgroundThe zebrafish retina maintains two populations of stem cells: first, the germinal zone or ciliary marginal zone (CMZ) contains multipotent retinal progenitors that add cells to the retinal periphery as the fish continue to grow; second, radial glia (Müller cells) occasionally divide asymmetrically to generate committed progenitors that differentiate into rod photoreceptors, which are added interstitially throughout the retina with growth. Retinal injury stimulates Müller glia to dedifferentiate, re-enter the cell cycle, and generate multipotent retinal progenitors similar to those in the CMZ to replace missing neurons. The specific signals that maintain these two distinct populations of endogenous retinal stem cells are not understood.ResultsWe used genetic and pharmacological manipulation of the ?-catenin/Wnt signaling pathway to show that it is required to maintain proliferation in the CMZ and that hyperstimulation of ?-catenin/Wnt signaling inhibits normal retinal differentiation and expands the population of proliferative retinal progenitors. To test whether similar effects occur during regeneration, we developed a method for making rapid, selective photoreceptor ablations in larval zebrafish with intense light. We found that dephosphorylated ?-catenin accumulates in Müller glia as they re-enter the cell cycle following injury, but not in Müller glia that remain quiescent. Activation of Wnt signaling is required for regenerative proliferation, and hyperstimulation results in loss of Müller glia from the INL as all proliferative cells move into the ONL.Conclusions?-catenin/Wnt signaling is thus required for the maintenance of retinal progenitors during both initial development and lesion-induced regeneration, and is sufficient to prevent differentiation of those progenitors and maintain them in a proliferative state. This suggests that the ?-catenin/Wnt cascade is part of the shared molecular circuitry that maintains retinal stem cells for both homeostatic growth and epimorphic regeneration.

Dataset Information

Dicer is required for the transition from early to late progenitor state in the developing mouse retina.

Publications

Dicer is required for the transition from early to late progenitor state in the developing mouse retina.

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