SOCS3 Is Required to Temporally Fine-Tune Photoreceptor Cell Differentiation

Abstract

Purpose:: To investigate the role of suppressor of cytokine signaling 3 (SOCS3), an intracellular, ligand-induced negative feedback modulator of STAT3 activation that acts during inflammation, in the photoreceptor cell differentiation.

Methods:: Expression of SOCS3 protein and mRNA during perinatal period were shown, when rod photoreceptor cells start to differentiate. Retinal explants derived from neonatal mice (P0 retinal explants) were transfected with dominant-negative form of SOCS3 to analyze the influence on Rhodopsin expression. Then, the contribution of SOCS3 in rod photoreceptor cell differentiation in vivo was analyzed using SOCS3-deficient mice.

Results:: SOCS3 protein expression was first detected postnatally, after STAT3 activation was mostly downregulated at P0, presumably by the depletion of upstream ligands. It initially appeared in some of the presumptive photoreceptor cells and gradually spread. SOCS3 mRNA level was constant from the late-embryonic to early-postnatal period. We demonstrated that SOCS3 was required after P0 to shutdown the residual STAT3 activation; this loss of activated STAT3 leads to Rhodopsin expression and rod photoreceptor cell differentiation. SOCS3 deficiency failed to terminate STAT3 activation, thereby delaying expression of Rhodopsin and its upstream transcription factor, crx. Development subsequently continued, but its course was temporally erratic, probably because of faulty compensation.

Conclusions:: Post-transcriptional inhibition of SOCS3 protein expression maintains a high STAT3 activation during late embryogenesis, and after P0, releasing from the inhibition promptly terminates STAT3 activation. SOCS3 can act as a temporal fine-tuner of STAT3 activation during photoreceptor cell differentiation.

Keywords: retinal development • differentiation • transgenics/knock-outs