Regulation of Rod Phototransduction Machinery by Ciliary Neurotrophic Factor

Abstract

Ciliary neurotrophic factor (CNTF) promotes photoreceptor survival but also suppresses electroretinogram (ERG) responses. This has caused concerns about whether CNTF is detrimental to the function of photoreceptors because it is considered to be a potential treatment for retinal degenerative disorders. Here we report that the suppression of ERG responses is attributable to negative regulation of the phototransduction machinery in rod photoreceptors. Intravitreal injection of recombinant human CNTF protein in rat results in a series of biochemical and morphological changes in rod photoreceptors. CNTF induces a decrease in rhodopsin expression and an increase in arrestin level. Morphologically, CNTF treatment causes a shortening of rod outer segments (ROS). All of these changes are fully reversible. The lower rhodopsin level and shortened ROS reduce the photon catch of rods. Less rhodopsin and more arrestin dramatically increase the arrestin-to-rhodopsin ratio so that more arrestin molecules are available to quench the photoexcited rhodopsin. The overall effect of CNTF is to negatively regulate the phototransduction machinery, which reduces the photoresponsiveness of rods, resulting in lower ERG amplitude at a given intensity of light stimulus. The CNTF-induced changes in rods are similar to those in light-induced photoreceptor plasticity. Whether CNTF-induced changes in rods are through the same mechanism that mediates light-induced photoreceptor plasticity remains to be answered.

Gene Therapy of Inherited Retinopathies: A Long and Successful Road from Viral Vectors to Patients

“…A paradigmatic example of gene supply is CNTF, which has been tested in a phase I safety trial (NCT00063765) by intraocular release in IR patients using encapsulatedcell implants (Sieving et al, 2006). Despite minor improvements in visual acuity in the absence of severe adverse effects, significant reductions in electroretinogram (ERG) were reported (Sieving et al, 2006), confirming what was previously observed in preclinical studies (Bok et al, 2002;Schlichtenbrede et al, 2003b;Wen et al, 2006). The detrimental effects observed following the intraocular delivery of high CNTF doses highlight the importance of regulating the expression of molecules with growth/neurotrophic/antiapoptotic activities, which may have tight therapeutic ranges.…”

Reprogramming of adult rod photoreceptors prevents retinal degeneration

“…Although these cells are not true cones, they exhibit sufficient down-regulation of rodspecific genes to resist the deleterious effects of a rod-specific mutation. Interestingly, some of the rod gene expression changes induced by acute Nrl KO are similar to those seen following treatment of the retina with ciliary neurotrophic factor (CNTF) (47). This observation suggests that these two manipulations, acute Nrl KO and CNTF delivery, may preserve rod photoreceptors via a related pathway.…”

CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells

“…Molecular and cellular analyses have demonstrated that persistent CNTF-induced signaling alters the retinal transcriptome, including reduced expression of genes involved in phototransduction and severe suppression of cone opsins (25,28). However, single intravitreal injection of CNTF results in transient but reversible shortening of the photoreceptor outer segments and perturbation of phototransduction genes (29).…”