Downregulation of STAT3 Activation Is Required for Presumptive Rod Photoreceptor Cells to Differentiate in the Postnatal Retina

Abstract

Abstract: : Purpose: To investigate the negative effect of intracellular signaling of CNTF/gp130 receptor, JAK/STAT pathway, on rod photoreceptor cell differentiation. Methods: Retinal explants derived from P0 mice (P0 retinal explants) were made from wild–type mice, STAT3–deficient mice, and gp130/SHP2 signal–deficient mice and investigated the effect of additional CNTF on rod photoreceptor cell differentiation. Electroporation of dominant–negative form of STAT3 (STAT3F) into the wild–type P0 retinal explants was also performed to confirm the results. Then the contribution of activated STAT3 on rod photoreceptor cell differentiation was analyzed in vivo using STAT3–deficient mice. Results:STAT3 activation, but not SHP2 activation, was responsible for the CNTF/gp130 signaling that inhibits expression of Rhodopsin and its upstream activator, crx in P0 retinal explants. We also demonstrated that STAT3 activation in presumptive rod photoreceptor cells at E18.5 is rapidly downregulated at P0, when Rhodopsin expression starts during retinal development. STAT3–deficient retinas did not exhibit precocious rod photoreceptor cell differentiation as a whole, although they occasionally exhibited precocious upregulation of crx mRNA. Conclusions: Persistent STAT3 activation in the P0 retinal explants prevented Rhodopsin expression and rapid upregulation of crx expression. Downregulation of STAT3 activation is required, but insufficient, for rod photoreceptor cell differentiation in the postnatal retina.

Keywords: retinal development • photoreceptors • signal transduction