RasGRF2 as a key regulator of cone photoreceptor function.
Alberto Fernández Medarde
Centro de Investigación del Cáncer (IBMCC, USAL-CSIC), Salamanca
The RasGRF family of guanine nucleotide exchange factors GRF1 and GRF2 play important functions in the mouse retina. Recently, using GRF2 knockout (KO) mice, we found that cone nuclear migration occurring during the so called “late migratory phase” is regulated by GRF2. Accompanying the deregulated cone nuclear movement, we found alterations in the electrophysiological responses of cone photoreceptor cells in the GRF2 KO retinas. Here we describe the effects of removing Rac1 or Cdc42, two GTPases regulated by GRF proteins, from cone photoreceptor cells, individually or in combination with GRF2. Whereas elimination of Rac1 from cone cells has no effect in cone morphology or physiology, and its combined elimination with GRF2 does not alter GRF2 KO phenotype, Cdc42 KO retinas present alterations in nuclear movement of the cone cells during the late migratory phase, but they lack alterations in the electrophysiology or survival of these cells. Moreover, we describe a slow progressive cone degeneration occurring in the GRF2 KO animals, a previously unseen effect of removing GRF2 from the retina. This was also found in the GRF2-Cdc42 double KO mice, which surprisingly showed normal nuclear cone movement and reduced electrophysiological responses, but cone cell degeneration was faster than in the GRF2 KO mice. Cell death was accompanied in both genotypes with structural alterations in the cone synapses. These results point to GRF2 as a key player in the physiology of cone photoreceptors and open the possibility of GRF2 mutations causing cone retinal dystrophies.