Abstract
Rbfox1 is a multifunctional RNA binding protein that regulates alternative splicing, transcription, mRNA stability and translation. Its roles in neurogenesis and neuronal functions are well established. Recent studies also implicate Rbfox1 in the regulation of gene networks that support cell survival during stress. We have earlier characterized the expression of Rbfox1 in amacrine and retinal ganglion cells (RGCs) and showed that deletion of Rbfox1 in adult animals results in depth perception deficiency. The current study investigates the effect of Rbfox1 downregulation on survival of RGCs injured by optic nerve crush (ONC). Seven days after ONC, animals sustained severe degeneration of RGC axons in the optic nerve and significant loss of RGC somas. Semi-quantitative grading of optic nerve damage in control + ONC, control + tamoxifen + ONC, and Rbfox1–/– + ONC groups ranged from 4.6 to 4.8 on a scale of 1 (normal; no degenerated axons were noted) to 5 (total degeneration; all axons showed degenerated organelles, axonal content, and myelin sheath), indicating a severe degeneration. Among these three ONC groups, no statistical significance was observed when any two groups were compared. The number of RGC somas were quantitatively analyzed in superior, inferior, nasal and temporal retinal quadrants at 0.5, 1, and 1.5 mm from the center of the optic disc. The average RGC densities (cells/mm2) were: control 6,438 ± 1,203; control + ONC 2,779 ± 573; control + tamoxifen 6,163 ± 861; control + tamoxifen + ONC 2,573 ± 555; Rbfox1–/– 6,437 ± 893; and Rbfox1–/– + ONC 2,537 ± 526. The RGC loss in control + ONC, control + tamoxifen + ONC and Rbfox1–/– + ONC was 57% (P = 1.44954E-42), 58% (P = 1.37543E-57) and 61% (P = 5.552E-59) compared to RGC numbers in the relevant uninjured groups, respectively. No statistically significant difference was observed between any two groups of uninjured animals or between any two ONC groups. Our data indicate that Rbfox1-mediated pathways have no effect on survival of RGCs injured by ONC.
Highlights
The RNA binding protein, fox-1 (Rbfox) homolog family includes three evolutionarily conserved multifunctional proteins, Rbfox1, Rbfox2, and Rbfox3, that regulate RNA metabolism, including alternative splicing, transcription, mRNA stability and translation efficiency
We showed that in both developing and mature retinas, Rbfox1 expression is restricted to retinal ganglion cells (RGCs) and amacrine cells (ACs)
Rbfox1 expression in mouse retinas was localized to RGCs and dACs in the ganglion cell layer (GCL) and innermost row of ACs in the inner nuclear layer (INL; Figures 1, 2)
Summary
The RNA binding protein, fox-1 (Rbfox) homolog family includes three evolutionarily conserved multifunctional proteins, Rbfox, Rbfox, and Rbfox, that regulate RNA metabolism, including alternative splicing, transcription, mRNA stability and translation efficiency. We have analyzed the expression of Rbfox in adult and differentiating mouse retinas and the effects of downregulation of this protein on visual function and the retinal transcriptome (Gu et al, 2018). Rbfox has been implicated in neuroprotective effect of miR132 against amyloid β-peptide (Aβ) and glutamate excitotoxicity in Alzheimer’s disease (El Fatimy et al, 2018) Based on these observations, we hypothesize that retinal cells that normally express Rbfox, such as RGCs, will be more susceptible to the stress and damage in the Rbfox KO animals compared with the wild-type. The current study evaluates the effect of Rbfox downregulation on the survival of RGCs in response to optic nerve crush (ONC), an established procedure for acute injury of RGC axons, which leads to severe and specific degeneration of RGC axons and somata
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