Abstract
ABSTRACTProtein inhibitor of activated Stat 3 (Pias3) is implicated in guiding specification of rod and cone photoreceptors through post-translational modification of key retinal transcription factors. To investigate its role during retinal development, we deleted exon 2-5 of the mouse Pias3 gene, which resulted in complete loss of the Pias3 protein. Pias3−/− mice did not show any overt phenotype, and retinal lamination appeared normal even at 18 months. We detected reduced photopic b-wave amplitude by electroretinography following green light stimulation of postnatal day (P)21 Pias3−/− retina, suggesting a compromised visual response of medium wavelength (M) cones. No change was evident in response of short wavelength (S) cones or rod photoreceptors until 7 months. Increased S-opsin expression in the M-cone dominant dorsal retina suggested altered distribution of cone photoreceptors. Transcriptome profiling of P21 and 18-month-old Pias3−/− retina revealed aberrant expression of a subset of photoreceptor genes. Our studies demonstrate functional redundancy in SUMOylation-associated transcriptional control mechanisms and identify a specific, though limited, role of Pias3 in modulating spatial patterning and optimal function of cone photoreceptor subtypes in the mouse retina.
Highlights
The vertebrate retina is designed to maximize the capture, integration, and transmission of visual information and consists of a stratified architecture with three cellular layers that include six neuronal cell types (Lamb, 2013)
A targeting vector with LoxP sites spanning exon 2 to 5 of the Protein inhibitor of activated Stat 3 (Pias3) gene and neomycin selection marker flanked by FRT sites was used to establish a germline knockout mouse line on C57BL/6J background (Pias3−/−)
The maximum response of P21 Pias3−/− mice to green stimuli (M-cone mediated) was impaired [203.6±6.1 versus 167.4±15.3 μv, P=0.0158] and remained so at least until 12 months (Figs 2D and 3). These results suggest an early and predominantly M-cone defect, with gradual decline of rod and S-cone function at older ages, in the absence of Pias3
Summary
The vertebrate retina is designed to maximize the capture, integration, and transmission of visual information and consists of a stratified architecture with three cellular layers that include six neuronal cell types (Lamb, 2013). These results suggested a dual role of Pias3 in rod and cone photoreceptor development through modulation of distinct targets in each cell type. Pias3−/− mice exhibited altered dorsoventral gradient of S-opsin, reduced M-cone-mediated visual response, and misregulation of a subset of vision-related genes, highlighting a specific role of Pias3 in establishing dorsoventral patterning and visual response of cone photoreceptors in the mouse retina.
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