Heterochronic misexpression of Ascl1 in the Atoh7 retinal cell lineage blocks cell cycle exit

Hufnagel, Robert B.; Riesenberg, Amy N.; Quinn, Malgorzata E.; Brzezinski, Joseph A.; Gläser, Thomas; Brown, Nadean L.

doi:10.1016/j.mcn.2013.02.004

Cited by 21 publications

(13 citation statements)

References 76 publications

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“…He et al () proposed that the decision of an RPC to withdraw from the cell cycle, enter G0, and commit to a retinal cell fate is governed by simple stochastic fluctuations in gene expression. Notably, cell cycle exit during early retinogenesis correlates with the initial expression of Atoh7 (Le et al, ; Hufnagel et al, ). That Atoh7 expression arises immediately after cell cycle exit suggests that this expression is also coupled to a stochastic event.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome of Atoh7 retinal progenitor cells identifies new Atoh7‐dependent regulatory genes for retinal ganglion cell formation

Gao

Mao

Pan

et al. 2014

Developmental Neurobiology

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Summary The bHLH transcription factor ATOH7 (Math5) is essential for establishing retinal ganglion cell (RGC) fate. However, Atoh7-expressing retinal progenitor cells (RPCs) can give rise to all retinal cell types, suggesting that other factors are involved in specifying RGCs. The basis by which a subpopulation of Atoh7-expressing RPCs commits to an RGC fate remains uncertain but is of critical importance to retinal development since RGCs are the earliest cell type to differentiate. To better understand the regulatory mechanisms leading to cell-fate specification, a binary genetic system was generated to specifically label Atoh7-expressing cells with GFP. FACS-purified GFP+ and GFP- cells were profiled by RNA-seq. Here, we identify 1,497 transcripts that were differentially expressed between the two RPC populations. Pathway analysis revealed diminished growth factor signaling in Atoh7-expressing RPCs, indicating that these cells had exited the cell cycle. In contrast, axon guidance signals were enriched, suggesting that axons of Atoh7-expressing RPCs were already making synaptic connections. Notably, many genes enriched in Atoh7-expressing RPCs encoded transcriptional regulators, and several were direct targets of ATOH7, including, and unexpectedly, Ebf3 and Eya2. We present evidence for a Pax6-Atoh7-Eya2 pathway that acts downstream of Atoh7 but upstream of differentiation factor Pou4f2. EYA2 is a protein phosphatase involved in protein-protein interactions and posttranslational regulation. These properties, along with Eya2 as an early target gene of ATOH7, suggest that EYA2 functions in RGC specification. Our results expand current knowledge of the regulatory networks operating in Atoh7-expressing RPCs and offer new directions for exploring the earliest aspects of retinogenesis.

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Section: Introductionmentioning

confidence: 99%

Transcriptome of Atoh7 retinal progenitor cells identifies new Atoh7‐dependent regulatory genes for retinal ganglion cell formation

Gao

Mao

Pan

et al. 2014

Developmental Neurobiology

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“…Cone photoreceptors occur in normal numbers in Neurog2/Ngn2 mutants but are increased in Atoh7/Math5 mutants. This increase is not prevented by Ascl1/Mash1 expressed from the Atoh7/Math5 locus (Hufnagel et al 2013).…”

Section: Sox and Proneural Bhlh Proteins In Neuron And Hair Cell Prodmentioning

confidence: 88%

Can the ‘neuron theory’ be complemented by a universal mechanism for generic neuronal differentiation

Ernsberger

2014

Cell Tissue Res

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With the establishment of the 'neuron theory' at the turn of the twentieth century, this remarkably powerful term was introduced to name a breathtaking diversity of cells unified by a characteristic structural compartmentalization and unique information processing and propagating features. At the beginning of the twenty-first century, developmental, stem cell and reprogramming studies converged to suggest a common mechanism involved in the generation of possibly all vertebrate, and at least a significant number of invertebrate, neurons. Sox and, in particular, SoxB and SoxC proteins as well as basic helix-loop-helix proteins play major roles, even though their precise contributions to progenitor programming, proliferation and differentiation are not fully resolved. In addition to neuronal development, these transcription factors also regulate sensory receptor and endocrine cell development, thus specifying a range of cells with regulatory and communicative functions. To what extent microRNAs contribute to the diversification of these cell types is an upcoming question. Understanding the transcriptional and post-transcriptional regulation of genes coding for cell type-specific cytoskeletal and motor proteins as well as synaptic and ion channel proteins, which mark differences but also similarities between the three communicator cell types, will provide a key to the comprehension of their diversification and the signature of 'generic neuronal' differentiation. Apart from the general scientific significance of a putative universal core instruction for neuronal development, the impact of this line of research for cell replacement therapy and brain tumor treatment will be of considerable interest.

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“…Interestingly, this outcome is not the same as ectopic expression of Ascl1 in the Atoh7 lineage. In that gene replacement mouse, both cell cycle exit and RGC differentiation were blocked, and the Atoh7 Ascl1KI/+ RPCs uniquely underwent extra rounds of mitosis (Hufnagel et al, 2013). Although the phenotypes of Atoh7 Ascl1KI/+ and Neurog2 Ascl1KI/GFP mice differed, in both situations ectopic Ascl1 expression induced cell cycle progression.…”

Section: Resultsmentioning

confidence: 99%

Integral bHLH factor regulation of cell cycle exit and RGC differentiation

Maurer

Kowalchuk

Shoja‐Taheri

et al. 2018

Developmental Dynamics

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Our data support the hypothesis that Neurog2 acts at the top of a retinal bHLH transcription factor hierarchy. The combined expression levels of these downstream factors are sufficiently induced by ectopic Ascl1 to restore RGC genesis, highlighting the robustness of this gene network during retinal ganglion cell neurogenesis. Developmental Dynamics 247:965-975, 2018. © 2018 Wiley Periodicals, Inc.

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Heterochronic misexpression of Ascl1 in the Atoh7 retinal cell lineage blocks cell cycle exit

Cited by 21 publications

References 76 publications

Transcriptome of Atoh7 retinal progenitor cells identifies new Atoh7‐dependent regulatory genes for retinal ganglion cell formation

Transcriptome of Atoh7 retinal progenitor cells identifies new Atoh7‐dependent regulatory genes for retinal ganglion cell formation

Can the ‘neuron theory’ be complemented by a universal mechanism for generic neuronal differentiation

Integral bHLH factor regulation of cell cycle exit and RGC differentiation

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