Integral bHLH factor regulation of cell cycle exit and RGC differentiation

Maurer, Kate A.; Kowalchuk, Angelica M.; Shoja‐Taheri, Farnaz; Brown, Nadean L.

doi:10.1002/dvdy.24638

Cited by 10 publications

(8 citation statements)

References 88 publications

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“…Alternatively, Neurog2 is known to control cell cycle exit in the brain, via its stimulation of the cyclin-dependent kinase inhibitor p27/Kip1(Cdkn1b) (Farah et al, 2000; Lacomme et al, 2012; Nguyen et al, 2006). In E12.5 Neurog2 germline mutants, we found a longer than normal cell cycle (Maurer et al, 2018), thereby pushing the window for retinal ganglion cell differentiation. Thus, a delay in any retinal neuron birthdate might bias the genesis of relatively later cell types.…”

Section: Discussionmentioning

confidence: 81%

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Requirements for Neurogenin2 during mouse postnatal retinal neurogenesis

Kowalchuk

Maurer

Shoja‐Taheri

et al. 2018

Developmental Biology

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During embryonic retinal development, the bHLH factor Neurog2 regulates the temporal progression of neurogenesis, but no role has been assigned for this gene in the postnatal retina. Using Neurog2 conditional mutants, we found that Neurog2 is necessary for the development of an early, embryonic cohort of rod photoreceptors, but also required by both a subset of cone bipolar subtypes, and rod bipolars. Using transcriptomics, we identified a subset of downregulated genes in P2 Neurog2 mutants, which act during rod differentiation, outer segment morphogenesis or visual processing. We also uncovered defects in neuronal cell culling, which suggests that the rod and bipolar cell phenotypes may arise via more complex mechanisms rather than a simple cell fate shift. However, given an overall phenotypic resemblance between Neurog2 and Blimp1 mutants, we explored the relationship between these two factors. We found that Blimp1 is downregulated between E12-birth in Neurog2 mutants, which probably reflects a dependence on Neurog2 in embryonic progenitor cells. Overall, we conclude that the Neurog2 gene is expressed and active prior to birth, but also exerts an influence on postnatal retinal neuron differentiation.

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Section: Discussionmentioning

confidence: 81%

“…In a separate study about the initial wave of retinal neurogenesis, we performed a transcriptomics analysis of purified GFP+ RPCs from E12.5 Neurog2 GFP/ + and Neurog2 GFP/GFP eyes (Maurer et al, 2018). Here Blimp1 mRNA levels were already significantly reduced in the absence of Neurog2 (n = 3 biologic replicates/genotype).…”

Section: Resultsmentioning

confidence: 99%

Requirements for Neurogenin2 during mouse postnatal retinal neurogenesis

Kowalchuk

Maurer

Shoja‐Taheri

et al. 2018

Developmental Biology

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“…However, further investigation is required to identify and characterize Nhlh1(+) developing cone photoreceptors and determine whether they develop from the ECR65(+) population. Similarly, NeuroG2 has been found to be important for RGC genesis [18,30] and involved in HC fate choice [2]. This role may underlie its interaction with ECR9 ( Fig.…”

Section: Discussionmentioning

confidence: 90%

Cis-regulatory analysis of Onecut1 expression in fate-restricted retinal progenitor cells

et al. 2020

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Background: The vertebrate retina consists of six major classes of neuronal cells. During development, these cells are generated from a pool of multipotent retinal progenitor cells (RPCs) that express the gene Vsx2. Fate-restricted RPCs have recently been identified, with limited mitotic potential and cell fate possibilities compared to multipotent RPCs. One population of fate-restricted RPCs, marked by activity of the regulatory element ThrbCRM1, gives rise to both cone photoreceptors and horizontal cells. These cells do not express Vsx2, but co-express the transcription factors (TFs) Onecut1 and Otx2, which bind to ThrbCRM1. The components of the gene regulatory networks that control the transition from multipotent to fate-restricted gene expression are not known. This work aims to identify and evaluate cis-regulatory elements proximal to Onecut1 to identify the gene regulatory networks involved in RPC fate-restriction. Method: We identified regulatory elements through ATAC-seq and conservation, followed by reporter assays to screen for activity based on temporal and spatial criteria. The regulatory elements of interest were subject to deletion and mutation analysis to identify functional sequences and evaluated by quantitative flow cytometry assays. Finally, we combined the enhancer::reporter assays with candidate TF overexpression to evaluate the relationship between the TFs, the enhancers, and early vertebrate retinal development. Statistical tests included ANOVA, Kruskal-Wallis, or unpaired t-tests.Results: Two regulatory elements, ECR9 and ECR65, were identified to be active in ThrbCRM1(+) restricted RPCs. Candidate bHLH binding sites were identified as critical sequences in both elements. Overexpression of candidate bHLH TFs revealed specific enhancer-bHLH interactions. Nhlh1 overexpression expanded ECR65 activity into the Vsx2(+) RPC population, and overexpression of NeuroD1/NeuroG2/NeuroD4 had a similar effect on ECR9. Furthermore, bHLHs that were able to activate ectopic ECR9 reporter were able to induce endogenous Otx2 expression. (Continued on next page)Conclusions: This work reports a large-scale screen to identify spatiotemporally specific regulatory elements near the Onecut1 locus. These elements were used to identify distinct populations in the developing retina. In addition, faterestricted regulatory elements responded differentially to bHLH factors, and suggest a role for retinal bHLHs upstream of the Otx2 and Onecut1 genes during the formation of restricted RPCs from multipotent RPCs.

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“…In particular, Atoh7 is one of the first pro-neuronal transcription factors and is essential for the production of the first neurons, RGC, in the zebrafish retina (Kay et al, 2001;Masai et al, 2000). Thus, it suggested that cells of this cluster were undergoing initiation of the neuronal differentiation program (Chiodini et al, 2013;Maurer et al, 2018). This cluster of cells constituted only a small fraction of 24-hpf RPCs (4.7%, Fig.…”

Section: Defining Cellular Heterogeneity Of Embryonic Rpcsmentioning

confidence: 99%

Unifying Developmental Programs for Embryonic and Post-Embryonic Neurogenesis in the Zebrafish Retina

Tang

Jin

et al. 2020

Development

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The zebrafish retina grows for a lifetime. Whether embryonic and postembryonic retinogenesis conform to the same developmental program is an outstanding question that remains under debate. Using single-cell RNA sequencing of ∼20,000 cells of the developing zebrafish retina at four different stages, we identified seven distinct developmental states. Each state explicitly expresses a gene set. Disruption of individual state-specific marker genes results in various defects ranging from small eyes to the loss of distinct retinal cell types. Using a similar approach, we further characterized the developmental states of postembryonic retinal stem cells (RSCs) and their progeny in the ciliary marginal zone. Expression pattern analysis of state-specific marker genes showed that the developmental states of postembryonic RSCs largely recapitulated those of their embryonic counterparts, except for some differences in rod photoreceptor genesis. Thus, our findings reveal the unifying developmental program used by the embryonic and postembryonic retinogenesis in zebrafish.

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Integral bHLH factor regulation of cell cycle exit and RGC differentiation

Cited by 10 publications

References 88 publications

Requirements for Neurogenin2 during mouse postnatal retinal neurogenesis

Requirements for Neurogenin2 during mouse postnatal retinal neurogenesis

Cis-regulatory analysis of Onecut1 expression in fate-restricted retinal progenitor cells

Unifying Developmental Programs for Embryonic and Post-Embryonic Neurogenesis in the Zebrafish Retina

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