Neurog2 controls the leading edge of neurogenesis in the mammalian retina

Departments of Pediatrics and Ophthalmology, Division of Developmental Biology, Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Developmental Biology (Impact Factor: 3.55). 02/2010; 340(2):490-503. DOI: 10.1016/j.ydbio.2010.02.002
Source: PubMed

ABSTRACT In the mammalian retina, neuronal differentiation begins in the dorso-central optic cup and sweeps peripherally and ventrally. While certain extrinsic factors have been implicated, little is known about the intrinsic factors that direct this process. In this study, we evaluate the expression and function of proneural bHLH transcription factors during the onset of mouse retinal neurogenesis. Dorso-central retinal progenitor cells that give rise to the first postmitotic neurons express Neurog2/Ngn2 and Atoh7/Math5. In the absence of Neurog2, the spread of neurogenesis stalls, along with Atoh7 expression and RGC differentiation. However, neurogenesis is eventually restored, and at birth Neurog2 mutant retinas are reduced in size, with only a slight increase in the retinal ganglion cell population. We find that the re-establishment of neurogenesis coincides with the onset of Ascl1 expression, and that Ascl1 can rescue the early arrest of neural development in the absence of Neurog2. Together, this study supports the hypothesis that the intrinsic factors Neurog2 and Ascl1 regulate the temporal progression of retinal neurogenesis by directing overlapping waves of neuron formation.

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Available from: Robert B Hufnagel, Sep 25, 2015
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    • "Most Ascl1 gain and loss of function analyses in the retina have so far uncovered phenotypes predominantly related to its proneural activity. Ascl1 has indeed been shown to be required for neuronal versus glial fate decisions during late neurogenesis [21], [22], [23], [71] and to participate, with other proneural genes, to the spatiotemporal progression of the neurogenic wave in the retina [72]. In line with this, recent lineage experiments in mouse revealed that Ascl1-expressing progenitors contribute to all major cell types of the retina with the exception of ganglion cells [3]. "
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    ABSTRACT: In contrast with the wealth of data involving bHLH and homeodomain transcription factors in retinal cell type determination, the molecular bases underlying neurotransmitter subtype specification is far less understood. Using both gain and loss of function analyses in Xenopus, we investigated the putative implication of the bHLH factor Ascl1 in this process. We found that in addition to its previously characterized proneural function, Ascl1 also contributes to the specification of the GABAergic phenotype. We showed that it is necessary for retinal GABAergic cell genesis and sufficient in overexpression experiments to bias a subset of retinal precursor cells towards a GABAergic fate. We also analysed the relationships between Ascl1 and a set of other bHLH factors using an in vivo ectopic neurogenic assay. We demonstrated that Ascl1 has unique features as a GABAergic inducer and is epistatic over factors endowed with glutamatergic potentialities such as Neurog2, NeuroD1 or Atoh7. This functional specificity is conferred by the basic DNA binding domain of Ascl1 and involves a specific genetic network, distinct from that underlying its previously demonstrated effects on catecholaminergic differentiation. Our data show that GABAergic inducing activity of Ascl1 requires the direct transcriptional regulation of Ptf1a, providing therefore a new piece of the network governing neurotransmitter subtype specification during retinogenesis.
    PLoS ONE 03/2014; 9(3):e92113. DOI:10.1371/journal.pone.0092113 · 3.23 Impact Factor
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    • "In mice lacking Neurog2, the neurogenic wave front stalls temporally resulting in disruption of RGC genesis and smaller retinas. The reinstatement of neurogenesis in Neurog2 mutants correlates with onset of expression of Ascl1, a later expressed bHLH transcription factor, suggesting functional redundancy between Neurog2 and Ascl1 (Hufnagel et al., 2010). FGF1 and the classical morphogen Sonic hedgehog (Shh) have also been implicated in driving the propagation of the RGC differentiation wave across the retina (McCabe et al., 1999; Neumann and Nuesslein-Volhard, 2000). "
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    ABSTRACT: The visual system is beautifully crafted to transmit information of the external world to visual processing and cognitive centers in the brain. For visual information to be relayed to the brain, a series of axon pathfinding events must take place to ensure that the axons of retinal ganglion cells, the only neuronal cell type in the retina that sends axons out of the retina, find their way out of the eye to connect with targets in the brain. In the past few decades, the power of molecular and genetic tools, including the generation of genetically manipulated mouse lines, have multiplied our knowledge about the molecular mechanisms involved in the sculpting of the visual system. Here, we review major advances in our understanding of the mechanisms controlling the differentiation of RGCs, guidance of their axons from the retina to the primary visual centers, and the refinement processes essential for the establishment of topographic maps and eye-specific axon segregation. Human disorders, such as albinism and achiasmia, that impair RGC axon growth and guidance and, thus, the establishment of a fully functioning visual system will also be discussed. The eyes together with their connecting pathways to the brain form the visual system. In the eye, the cornea bends light rays and is primarily responsible for focusing the image on the retina. The lens behind the cornea inverts the image top to bottom and right to left. The retina, the receptive surface inside the back of the eye, is the struc-ture that translates light into nerve signals, and enables us to see under conditions that range from dark to sunlight, discriminate colors, and provide a high degree of visual precision. The retina consists of three layers of nerve cell bodies separated by two layers containing synapses made by the axons and dendrites of these cells. The back of the retina comprises the photoreceptors, the rods, and cones. The medial retinal layer contains three types of nerve cells, bipolar, horizontal, and amacrine cells. Bipolar cells receive input from the photoreceptors, and many of them feed directly into the retinal ganglion cells (RGCs). Horizontal cells connect receptors and bipolar cells by relatively long connections that run parallel to the retinal layers. Amacrine cells link bipolar cells and RGCs, the cells located in the inner retina. RGC axons pass across the surface of the retina and are collected in a bundle at the optic disk to leave the eye and form the optic nerve. There are approximately 20 RGC types that can be classified by morphological, molecular, and func-tional criteria. Each RGC type participates in distinct retinal circuits and projects to a specific set of targets in the brain (Coombs et al., 2007; Schmidt et al., 2011), including the main image-forming nuclei such as the lat-eral geniculate nucleus (LGN), the visual part of the thal-amus, and the superior colliculus (SC), located in the roof of the midbrain, that coordinates rapid movement of the eye (Figure 1). The optic axons from both eyes meet at the optic chiasm, which is located at the base of the hypothalamus. There, RGC axons from the nasal retina cross over to the opposite side of the brain (contralateral or commissural axons) while axons from the temporal retina turn to
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    • "Indeed, the levels of Pax6 vary according to cell-cycle stage; cells in the G1 and S phase express low levels of Pax6, whereas cells in G2 and M may display either low levels, high levels or no Pax6 expression at all [58]. An additional level of complexity in deciphering the mechanism of Pax6 activity is that this TF also regulates the expression of differentiation factors, particularly that of bHLH proneural factors Ato7 [84,85], Neurog2 [86] and Ascl1 [6-8]. These differentiation-promoting TFs are thought to directly inhibit cell-cycle-promoting factors as was demonstrated for Neurog2 [4]), and thus their combined loss may contribute not only to the limited differentiation potential of Pax6-deficient RPCs but also to the persistent expression of Ccnd1 in the Pax6-deficient precursors. "
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    ABSTRACT: The coupling between cell-cycle exit and onset of differentiation is a common feature throughout the developing nervous system, but the mechanisms that link these processes are mostly unknown. Although the transcription factor Pax6 has been implicated in both proliferation and differentiation of multiple regions within the central nervous system (CNS), its contribution to the transition between these successive states remains elusive. To gain insight into the role of Pax6 during the transition from proliferating progenitors to differentiating precursors, we investigated cell-cycle and transcriptomic changes occurring in Pax6 (-) retinal progenitor cells (RPCs). Our analyses revealed a unique cell-cycle phenotype of the Pax6-deficient RPCs, which included a reduced number of cells in the S phase, an increased number of cells exiting the cell cycle, and delayed differentiation kinetics of Pax6 (-) precursors. These alterations were accompanied by coexpression of factors that promote (Ccnd1, Ccnd2, Ccnd3) and inhibit (P27 (kip1) and P27 (kip2) ) the cell cycle. Further characterization of the changes in transcription profile of the Pax6-deficient RPCs revealed abrogated expression of multiple factors which are known to be involved in regulating proliferation of RPCs, including the transcription factors Vsx2, Nr2e1, Plagl1 and Hedgehog signaling. These findings provide novel insight into the molecular mechanism mediating the pleiotropic activity of Pax6 in RPCs. The results further suggest that rather than conveying a linear effect on RPCs, such as promoting their proliferation and inhibiting their differentiation, Pax6 regulates multiple transcriptional networks that function simultaneously, thereby conferring the capacity to proliferate, assume multiple cell fates and execute the differentiation program into retinal lineages.
    PLoS ONE 09/2013; 8(9):e76489. DOI:10.1371/journal.pone.0076489 · 3.23 Impact Factor
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