Near complete loss of retinal ganglion cells in the math5/brn3b double knockout elicits severe reductions of other cell types during retinal development

Department of Biochemistry and Molecular Biology, The University of Texas-Houston, Houston, TX 77030, USA.
Developmental Biology (Impact Factor: 3.55). 05/2008; 316(2):214-27. DOI: 10.1016/j.ydbio.2008.01.015
Source: PubMed


Retinal ganglion cells (RGCs) are the first cell type to differentiate during retinal histogenesis. It has been postulated that specified RGCs subsequently influence the number and fate of the remaining progenitors to produce the rest of the retinal cell types. However, several genetic knockout models have argued against this developmental role for RGCs. Although it is known that RGCs secrete cellular factors implicated in cell proliferation, survival, and differentiation, until now, limited publications have shown that reductions in the RGC number cause significant changes in these processes. In this study, we observed that Math5 and Brn3b double null mice exhibited over a 99% reduction in the number of RGCs during development. This severe reduction of RGCs is accompanied by a drastic loss in the number of all other retinal cell types that was never seen before. Unlike Brn3b null or Math5 null animals, mice null for both alleles lack an optic nerve and have severe retinal dysfunction. Results of this study support the hypothesis that RGCs play a pivotal role in the late phase of mammalian retina development.

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    • "In an attempt to estimate the RGC number in the Atoh7−/−;Pou4f2−/− DKO retina, DiI gunning yielded no RGCs and there was no optic nerve, making retrograde dye tracing impossible. Therefore, RGC number was estimated by comparing neurofilament light chain (NF-L) positive cells in the RGC layer in flat-mounted retinas with that of Atoh7−/− retinas [9]. Estimates showed that each Atoh7−/−;Pou4f2−/− retina had less than one fifth of the number of NF-L-positive axons that were observed in the Atoh7−/− single mutant retina, which is corresponding to approximately less than 1% of normal RGC population. "
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    ABSTRACT: Retinal ganglion cells (RGCs) play important roles in retinogenesis. They are required for normal retinal histogenesis and retinal cell number balance. Developmental RGC loss is typically characterized by initial retinal neuronal number imbalance and subsequent loss of retinal neurons. However, it is not clear whether loss of a specific non-RGC cell type in the RGC-depleted retina is due to reduced cell production or subsequent degeneration. Taking advantage of three knockout mice with varying degrees of RGC depletion, we re-examined bipolar cell production in these retinas from various aspects. Results show that generation of the cone bipolar cells is correlated with the existing number of RGCs. However, generation of the rod bipolar cells is unaffected by RGC shortage. Results report the first observation that RGCs selectively influence the genesis of subsequent retinal cell types.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "However, more recent findings suggest that neither Math5, nor Brn3b are responsible for the entire set of RGC types. Thus, RGCs with well-preserved morphologies can be generated in the absence of either transcription factor [26], and a few RGCs survive combined ablation of both [27]. In addition, Isl1 is required for RGC differentiation in a pathway that is overlapping with Brn3b [28], [29] in a manner analogous to previously noted genetic interactions for the C. elegans and Drosophila homologues of Isl1 and Brn3s. "
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    ABSTRACT: Visual information is conveyed from the retina to the brain via 15-20 Retinal Ganglion Cell (RGC) types. The developmental mechanisms by which RGC types acquire their distinct molecular, morphological, physiological and circuit properties are essentially unknown, but may involve combinatorial transcriptional regulation. Brn3 transcription factors are expressed in RGCs from early developmental stages, and are restricted in adults to distinct, partially overlapping populations of RGC types. Previously, we described cell autonomous effects of Brn3b (Pou4f2) and Brn3a (Pou4f1) on RGC axon and dendrites development. We now have investigated genetic interactions between Brn3 transcription factors with respect to RGC development, by crossing conventional knock-out alleles of each Brn3 gene with conditional knock-in reporter alleles of a second Brn3 gene, and analyzing the effects of single or double Brn3 knockouts on RGC survival and morphology. We find that Brn3b loss results in axon defects and dendritic arbor area and lamination defects in Brn3a positive RGCs, and selectively affects survival and morphology of specific Brn3c (Pou4f3) positive RGC types. Brn3a and Brn3b interact synergistically to control RGC numbers. Melanopsin positive ipRGCs are resistant to combined Brn3 loss but are under the transcriptional control of Isl1, expanding the combinatorial code of RGC specification. Taken together these results complete our knowledge on the mechanisms of transcriptional control of RGC type specification. They demonstrate that Brn3b is required for the correct development of more RGC cell types than suggested by its expression pattern in the adult, but that several cell types, including some Brn3a, Brn3c or Melanopsin positive RGCs are Brn3b independent.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "BRN3B (POU4F2) is a transcription factor that is specifically expressed in RGCs, labeling ~80% of RGCs in the retina (Badea et al., 2009; Moshiri et al., 2008). It is important for RGC survival during development (Gan et al., 1999) and is downregulated very early after RGC injury before RGC death, including, after optic nerve injury (Pelzel et al., 2010; Weishaupt et al., 2005). "
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    ABSTRACT: Glaucoma is a neurodegenerative disease characterized by the apoptotic death of retinal ganglion cells (RGCs). The primary insult to RGCs in glaucoma is thought to occur to their axons as they exit the eye in the optic nerve head. However, pathological signaling pathways that exert central roles in triggering RGC death following axonal injury remain unidentified. It is likely that the first changes to occur following axonal injury are signal relay events that transduce the injury signal from the axon to the cell body. Here we focus on the c-Jun N-terminal kinase (JNK1-3) family, a signaling pathway implicated in axonal injury signaling and neurodegenerative apoptosis, and likely to function as a central node in axonal injury-induced RGC death. We show that JNK signaling is activated immediately after axonal injury in RGC axons at the site of injury. Following its early activation, sustained JNK signaling is observed in axonally-injured RGCs in the form of JUN phosphorylation and upregulation. Using mice lacking specific Jnk isoforms, we show that Jnk2 and Jnk3 are the isoforms activated in injured axons. Combined deficiency of Jnk2 and Jnk3 provides robust long-term protection against axonal injury-induced RGC death and prevents downregulation of the RGC marker, BRN3B, and phosphorylation of JUN. Finally, using Jun deficient mice, we show that JUN-dependent pathways are important for axonal injury-induced RGC death. Together these data demonstrate that JNK signaling is the major early pathway triggering RGC death after axonal injury and may directly link axon injury to transcriptional activity that controls RGC death.
    Full-text · Article · Feb 2012 · Neurobiology of Disease
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