CONICET | Buscador de Institutos y Recursos Humanos

Retinitis pigmentosa (RP) is an inherited degenerative retinal disease characterized by a progressive loss of photoreceptor that eventually culminates in irreversible blindness. Yet, the molecular mechanisms that lead to photoreceptor death have not been fully elucidated. Imbalance between full-length and truncated isoforms of Trk receptors are known to induce neuronal cell death. Here, we sought to determine whether the truncated isoform of the TrkC neurotrophin receptor, TrkC.T1, is relevant to the degeneration of photoreceptors during RP and investigate the intracellular signaling mechanisms underlying photoreceptor loss.A genetic model of engineered mice lacking TrkC.T1 crossed with a Rhodopsin mutant (RHOP347S) mouse model of RP was used to examine the effect of TrkC.T1 on the degeneration of the outer nuclear layer (ONL) and photoreceptor cell death. In RHOP:TrkC.T1+/+ mice, TrkC.T1 was up-regulated in the retinal cell layers where Müller glial cells are located. RHOP:TrkC.T1+/+ mice showed photoreceptor loss and progressive thinning of the ONL parallel to the activation of p-Erk in Müller cells and p-Akt in bipolar cells. Genetical ablation of only one TrkC.T1 allele (RHOP:TrkC.T1+/-) or pharmacological inhibition of TrkC in vivo and in vitro delayed ONL thinning, decreased photoreceptor cell death and inhibited p-Erk and p-Akt activation. Moreover, interfering with the MAPK/Erk pathway delayed degeneration of the ONL in RHOP:TrkC.T1+/+ mice. In addition, silencing TrkC.T1 mRNA prevented p-Erk activation, but not p-Akt, in cultured Müller cells. Taken together, these data indicates that TrkC.T1 receptor is implicated in photoreceptor cell loss during RP. The deleterious effect of TrkC.T1 up-regulation is mediated, at least in part, by the activation of downstream MAPK/Erk signaling cascade through a non-cell autologous or paracrine mechanism.