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


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,
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    • "Undoubtedly both extrinsic and intrinsic factors control these processes, but only a few genes are known, and their activities are insufficient to explain the underlying mechanisms. One intrinsic factor required for the progression of neurogenesis is Neurog2 (Hufnagel et al., 2010). Another is Pax6, which is expressed by all optic cup cells, exhibits multiple functions and yet is differentially required by distal optic cup cells. "
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    ABSTRACT: 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.
    Development 08/2014; 141(16):3243-54. DOI:10.1242/dev.106245 · 6.46 Impact Factor
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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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