RasGRF2 controls nuclear trafficking in photoreceptor cells

Abstract

Analyses of RasGRF1 knockout (GRF1-KO), GRF2-KO and the GRF1/2 double-KO mouse retinas, revealed specific alterations in cone photoreceptors in the GRF2-KO and GRF1/2-DKO. These alterations consist in the specific accumulation of misplaced “ectopic” nuclei in the photoreceptors segments area. The pathological displacement of cone nuclei occurred postnatally and peaked between postnatal day 11 (P11) and P15 coinciding with the so called “late migratory phase” of cone nuclei. The late migratory phase is a physiological process whereby cone nuclei move towards the outer limiting membrane (OLM) where they reach their final position. In the GRF2-KO and GRF1/2-DKO retinas this movement is deregulated and cone nuclei are located closer to the OLM and in some regions of the retina even trespass it. Using detailed inmunocytochemical analyses we have identified disruption of the OLM and accumulation of activated, phosphorylated forms of PAK, MLC2 and VASP, molecules known to participate in nuclear migration and cytoskeletal reorganization, in cone photoreceptors of GRF2-KO and GRF1/2-DKO retinas. Electroretinographic recordings show specific impairment of cone photoreceptor cells in GRF1-KO and GRF1/2-DKO retinas. These data support a critical role of GRF2 in cone nuclear migration and proper retinal development and functioning.