Pushing the envelope of retinal ganglion cell genesis: Context dependent function of Math5 (Atoh7)

Departments of Human Genetics and Internal Medicine, University of Michigan, 2047 BSRB, Box 2200, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
Developmental Biology (Impact Factor: 3.55). 05/2012; 368(2):214-30. DOI: 10.1016/j.ydbio.2012.05.005
Source: PubMed


The basic-helix-loop helix factor Math5 (Atoh7) is required for retinal ganglion cell (RGC) development. However, only 10% of Math5-expressing cells adopt the RGC fate, and most become photoreceptors. In principle, Math5 may actively bias progenitors towards RGC fate or passively confer competence to respond to instructive factors. To distinguish these mechanisms, we misexpressed Math5 in a wide population of precursors using a Crx BAC or 2.4 kb promoter, and followed cell fates with Cre recombinase. In mice, the Crx cone-rod homeobox gene and Math5 are expressed shortly after cell cycle exit, in temporally distinct, but overlapping populations of neurogenic cells that give rise to 85% and 3% of the adult retina, respectively. The Crx>Math5 transgenes did not stimulate RGC fate or alter the timing of RGC births. Likewise, retroviral Math5 overexpression in retinal explants did not bias progenitors towards the RGC fate or induce cell cycle exit. The Crx>Math5 transgene did reduce the abundance of early-born (E15.5) photoreceptors two-fold, suggesting a limited cell fate shift. Nonetheless, retinal histology was grossly normal, despite widespread persistent Math5 expression. In an RGC-deficient (Math5 knockout) environment, Crx>Math5 partially rescued RGC and optic nerve development, but the temporal envelope of RGC births was not extended. The number of early-born RGCs (before E13) remained very low, and this was correlated with axon pathfinding defects and cell death. Together, these results suggest that Math5 is not sufficient to stimulate RGC fate. Our findings highlight the robust homeostatic mechanisms, and role of pioneering neurons in RGC development.

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    • "Eliminating both Pax2 and Pax8 results in the severe truncation of ear development at the otocyst stage without any formation of neurosensory cells, indicating a molecularly unclear connection of Pax2/8 genes to the formation of ear ganglion cells, possibly via an interaction with Pou domain factors as in general neurogenesis (Zhu et al. 2014). Incidentally , Pax2 plays a similar role in retinal ganglion cell development (Cross et al. 2011; Torres et al. 1996), which requires the bHLH transcription factor Atoh7, an ortholog of the hair cell differentiation transcription factor Atoh1, for normal differentiation (Mao et al. 2013; Prasov and Glaser 2012). These similarities might be related to the conservation of these molecular cascades in the sense of deep homology (Shubin et al. 2009) for eye and ear development and evolution (Fritzsch and Piatigorsky 2005). "
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    ABSTRACT: The mammalian inner ear develops from a placodal thickening into a complex labyrinth of ducts with five sensory organs specialized to detect position and movement in space. The mammalian ear also develops a spiraled cochlear duct containing the auditory organ, the organ of Corti (OC), specialized to translate sound into hearing. Development of the OC from a uniform sheet of ectoderm requires unparalleled precision in the topological developmental engineering of four different general cell types, namely sensory neurons, hair cells, supporting cells, and general otic epithelium, into a mosaic of ten distinctly recognizable cell types in and around the OC, each with a unique distribution. Moreover, the OC receives unique innervation by ear-derived spiral ganglion afferents and brainstem-derived motor neurons as efferents and requires neural-crest-derived Schwann cells to form myelin and neural-crest-derived cells to induce the stria vascularis. This transformation of a sheet of cells into a complicated interdigitating set of cells necessitates the orchestrated expression of multiple transcription factors that enable the cellular transformation from ectoderm into neurosensory cells forming the spiral ganglion neurons (SGNs), while simultaneously transforming the flat epithelium into a tube, the cochlear duct, housing the OC. In addition to the cellular and conformational changes forming the cochlear duct with the OC, changes in the surrounding periotic mesenchyme form passageways for sound to stimulate the OC. We review molecular developmental data, generated predominantly in mice, in order to integrate the well-described expression changes of transcription factors and their actions, as revealed in mutants, in the formation of SGNs and OC in the correct position and orientation with suitable innervation. Understanding the molecular basis of these developmental changes leading to the formation of the mammalian OC and highlighting the gaps in our knowledge might guide in vivo attempts to regenerate this most complicated cellular mosaic of the mammalian body for the reconstitution of hearing in a rapidly growing population of aging people suffering from hearing loss.
    Cell and Tissue Research 11/2014; 384(1). DOI:10.1007/s00441-014-2031-5 · 3.57 Impact Factor
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    • "Therefore, we wondered whether the aberrant axon projections in Atoh7 Ascl1KI/Ascl1KI retinas indicated that mutant cells normally fated to become RGCs, instead die. We surveyed E12.5, E14.5 and E16.5 retinal sections from wild type, Atoh7 Ascl1KI/+ , and Atoh7 Ascl1KI/Ascl1KI eyes and found a rapid accumulation of activated-Caspase3+ cells only in Atoh7 Ascl1KI/Ascl1KI mutants from E12.5- E16.5 (Fig 5J-5M), which phenocopied Atoh7 mutants (Feng et al., 2010; Prasov et al., 2012). "
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    ABSTRACT: Retinal neurons and glia arise from a common progenitor pool in a temporal order, with retinal ganglion cells (RGCs) appearing first, and Müller glia last. The transcription factors Atoh7/Math5 and Ascl1/Mash1 represent divergent bHLH clades, and exhibit distinct spatial and temporal retinal expression patterns, with little overlap during early development. Here, we tested the ability of Ascl1 to change the fate of cells in the Atoh7 lineage when misexpressed from the Atoh7 locus, using an Ascl1-IRES-DsRed2 knock-in allele. In Atoh7Ascl1KI/+ and Atoh7Ascl1KI/Ascl1KI embryos, ectopic Ascl1 delayed cell cycle exit and differentiation, even in cells coexpressing Atoh7. The heterozygous retinas recovered, and eventually produced a normal complement of RGCs, while homozygous substitution of Ascl1 for Atoh7 did not promote postnatal retinal fates precociously, nor rescue Atoh7 mutant phenotypes. However, our analyses revealed two unexpected findings. First, ectopic Ascl1 disrupted cell cycle progression within the marked Atoh7 lineage, but also nonautonomously in other retinal cells. Second, the size of the Atoh7 retinal lineage was unaffected, supporting the idea of a compensatory shift of the non-proliferative cohort to maintain lineage size. Overall, we conclude that Ascl1 acts dominantly to block cell cycle exit, but is incapable of redirecting the fates of early RPCs.
    Molecular and Cellular Neuroscience 02/2013; 54. DOI:10.1016/j.mcn.2013.02.004 · 3.84 Impact Factor
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    ABSTRACT: The basic helix-loop-helix factor Math5 (Atoh7) is critical for the determination of retinal ganglion cell (RGC) fate in mice. Recently, genome-wide association studies have identified the ATOH7 locus as a major determinant of variation in the human optic disc area, which is directly correlated with the RGC number. These studies suggest that the level of Math5 expression may determine the ultimate number of RGCs. To test this hypothesis, we systematically compared optic nerve area and RGC axon number in C57BL/6J congenic Math5+/- and +/+ mice at young adult and neonatal ages by transmission electron microscopy. Optic disc area and RGC abundance were not significantly different in adults, but heterozygotes had thinner optic nerves and 25-30% fewer RGCs at birth than wild-type littermates (P<0.05). Our results suggest that Math5 dosage is important for the genesis, but not the ultimate number, of RGCs. Our findings highlight the importance of ganglion cell culling as a compensatory mechanism for retinal homeostasis, and support a quantitative role for Math5 in RGC specification.
    Neuroreport 07/2012; 23(10):631-4. DOI:10.1097/WNR.0b013e328355f260 · 1.52 Impact Factor
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