Photoreceptors in whirler mice show defective transducin translocation and are susceptible to short-term light/dark changes-induced degeneration

Abstract

Usher syndrome combines congenital hearing loss and retinitis pigmentosa (RP). Mutations in the whirlin gene (DFNB31/WHRN) cause a subtype of Usher syndrome (USH2D). Whirler mice have a defective whirlin gene. They have inner ear defects but usually do not develop retinal degeneration. Here we report that, in whirler mouse photoreceptors, the light-activated rod transducin translocation is delayed and its activation threshold is shifted to a higher level. Rhodopsin mis-localization is observed in rod inner segments. Continuous moderate light exposure can induce significant rod photoreceptor degeneration. Whirler mice reared under a 1500 lux light/dark cycle also develop severe photoreceptor degeneration. Previously, we have reported that shaker1 mice, a USH1B model, show moderate light-induced photoreceptor degeneration with delayed transducin translocation. Here, we further show that, in both whirler and shaker1 mice, short-term moderate light/dark changes can induce rod degeneration as severe as that induced by continuous light exposure. The results from shaker1 and whirler mice suggest that defective transducin translocation may be functionally related to light-induced degeneration, and these two symptoms may be caused by defects in Usher protein function in rods. Furthermore, these results indicate that both Usher syndrome mouse models possess a light-induced retinal phenotype and may share a closely related pathobiological mechanism.

Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities

“…Originally, the USH2 complex at the periciliary membrane complex was proposed to participate in protein trafficking through the connecting cilium [107], but no clear evidence demonstrates any defects in protein trafficking between the inner and outer segment in Ush2a −/− and Whrn neo/neo photoreceptors [106, 116]. Interestingly, using Whrn wi/wi mice, which do not develop spontaneous retinal degeneration [106], Tian et al demonstrated a defect in light-induced transducin translocation from photoreceptor outer to inner segment and light-induced retinal degeneration [160]. The molecular mechanisms underlying these phenotypes in Whrn wi/wi mice need to be further elucidated.…”

“…Further, cadherin 23, harmonin and clarin-1 proteins of various species show significantly different retinal cellular and subcellular patterns [97, 99, 112, 114, 115, 118, 119]. A third hypothesis is that light illumination is necessary to induce retinal degeneration in USH mouse models [153, 160], although the underlying mechanism is unclear. Recently, zebrafish models carrying USH gene mutations have emerged to exhibit early retinal degeneration phenotypes, such as myo7aa ty229d/ty229d and ush1c fh293/fh293 zebrafish [115, 151], indicating that zebrafish models could be useful for understanding functions of USH genes in the retina and testing potential treatments.…”

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

“…Dark-rearing has also been demonstrated to delay PR degeneration in Slc6a6 tm1Dhau (10% loss vs. 90% loss in normal vivarium lighting at three weeks of age) [473] or have no effect in C57BL/6-Mitf mi-vit /J homozygotes [474]. In some situations, light may actually trigger the disease phenotype, as is the case in Sag knockout mice [198,199], with three Class B1 Rhodopsin missense mutations, Tvrm1 and Tvrm4 [157] or Tvrm144 [18], and in null mutation models of Rdh12 [475], Asic2 [476], Myo7a [477], Whrn [478], or Akt2 [479]. Sag mutants must be reared in the dark to observe any PR cells.…”

Cul3‐Klhl18 ubiquitin ligase modulates rod transducin translocation during light‐dark adaptation

“…For example, transgenic mice expressing a mutant form of the α‐subunit of transducin (Tα), in which Tα acylation and localization to the outer segment are inhibited, show a decreased light sensitivity of rod photoreceptors (Kerov et al , ). In contrast, mouse lines modeling Usher syndrome, shaker1 and whirler , exhibit defective Tα translocation to the inner part and a decreased threshold of light‐triggered photoreceptor degeneration (Peng et al , ; Tian et al , ). Furthermore, additional lipid modification by an amino acid substitution partially blocks light‐induced Tα translocation from the outer segment to the inner part, leading to photoreceptor cell death (Kerov & Artemyev, ; Majumder et al , ).…”