cGMP‐dependent cone photoreceptor degeneration in the cpfl1 mouse retina

Abstract

Inherited retinal degeneration affecting both rod and cone photoreceptors constitutes one of the leading causes of blindness in the developed world. Such degeneration is at present untreatable, and the underlying neurodegenerative mechanisms are unknown, even though certain genetic causes have been established. The rd1 mouse is one of the best characterized animal models for rod photoreceptor degeneration, whereas the cpfl1 mouse is a recently discovered model for cone cell death. Because both animal models are affected by functionally similar mutations in the rod and cone phosphodiesterase 6 genes, respectively, we asked whether the mechanisms of photoreceptor degeneration in these two mouse lines share common pathways. In the present study, we followed the temporal progression of photoreceptor degeneration in the cpfl1 retina, correlated it with specific metabolic markers, and compared it with the wild-type and the rd1 situation. Similar to corresponding rd1 observations, cpfl1 cone photoreceptor cell death was associated with an accumulation of cyclic guanosine monophosphate (cGMP), activity of calpains, and phosphorylation of vasodilator-stimulated protein (VASP). Cone degeneration progressed rapidly, with a peak in cell death around postnatal day 24. Furthermore, cpfl1 cone photoreceptor migration during early postnatal development was delayed significantly compared with the corresponding wild-type retina. The finding that rod and cone photoreceptor degeneration was associated with the same metabolic markers suggests that in both cell types similar degenerative mechanisms are active. This raises the possibility that equivalent neuroprotective strategies may be used to prevent both rod and cone photoreceptor degeneration.

Rax Homeoprotein Regulates Photoreceptor Cell Maturation and Survival in Association with Crx in the Postnatal Mouse Retina

“…3Z). Mislocalization of cone photoreceptor cells in the retina has been shown to be associated with a disturbance of cone photoreceptor maturation and consequent degeneration (33,34). Furthermore, we observed that CreERT2 mRNA was predominantly expressed in the ONL of the Rax iCKO (P4 ¡ P14) mouse retinas (see Fig.…”

Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse

“…A similar phenotype of late NT deficiency has been described in the cone cyclic nucleotide-gated channel Cnga3 gene knockout mice (44), and a loss-of-function mutation of the gene coding for the catalytic subunit of cone-specific cGMP phosphodiesterase (Ped6c) in cpfl1 mice (45). Both Cnga3 and Ped6c genes are components of the vertebrate phototransduction cascade.…”

“…The cGMP-gated Cnga3 regulates cationic influx in cones, and Pde6 cleaves intracellular cGMP in response to phototransduction activation. Loss-of-function mutation in either Cnga3 or Pde6c led to intracellular accumulation of cGMP, which was linked to photoreceptor death (45,46). Whereas it is not known whether changes in intracellular cGMP levels in cones in either mutant played a role in the development of late-phase NT deficiency, it is conceivable that cGMP, an important second messenger, can impact many cellular homeostatic processes.…”

RasGRF2 controls nuclear migration in postnatal retinal cone photoreceptors

“…As many of these signaling molecules are potential targets or downstream effectors of GRF signaling, their study might provide clues to ascertain the exact molecular mechanisms responsible for the GRF2-dependent defects of cone nuclear movement described in this report. Nevertheless, we should also mention that, in contrast to most models of defective cone nuclear movement, where the cellular morphological alterations are usually accompanied by photoreceptor cell death (Pow and Sullivan, 2007;Song et al, 2014;Trifunovićet al, 2010), the cones of GRF2-KO retinas presented normal morphology and their survival was not compromised (at least until our analysis at 5 months of age), suggesting significant mechanistic proximity between GRF2 and control of cone nuclear movements, although further functional studies are needed to confirm this notion. Even if the survival of cone photoreceptors is not compromised in GRF2-depleted retinas, their defective ERG patterns clearly indicate that their functional role in the vision process is compromised, and it will be interesting to determine whether the reduced ERG responses are due to alterations in the synaptogenesis (Rich et al, 1997) of the cone cells in retinas lacking GRF2.…”

“…Previous studies of neuroepithelial differentiation and retinal degeneration processes occurring in mouse models (García Arguinzonis et al, 2002;Song et al, 2014;Trifunovićet al, 2010) or in humans (Jacobson et al, 2003;Lotery, 2001;Mehalow et al, 2003;Pow and Sullivan, 2007;van de Pavert et al, 2004van de Pavert et al, , 2007 have provided useful clues regarding the cellular mechanisms and signaling molecules that might be relevant for the origination of the novel GRF2-dependent phenotypes described in this report. Consistent with those reports, our immunolabeling analyses identified structural disruptions of the OLM and alterations of the expression patterns of several signaling molecules that were closely associated to the defective cone nuclear migration phenotype observed in GRF2-depleted retinas.…”