Abstract
Purpose :
Formation and functions of primary cilia, microtubule-based sensory organelles, depend on intraflagellar transport (IFT), which is composed of three steps: anterograde transport, turnaround at ciliary tips and retrograde transport. IFT dysfunction leads to ciliopathies in humans. However, the regulatory pathways of IFT remain largely unknown, and there is no effective therapy for most ciliopathies including retinal degenerative diseases. We explored the functional mechanisms of ciliary kinases in IFT regulation and the possibility of therapeutic treatment for ciliopathy-related retinal degeneration using ciliary kinase signaling.
Methods :
We performed molecular, cellular, histological, and electrophysiological analyses in combination with mouse genetics.
Results :
We found that the male germ cell-associated kinase (Mak) and intestinal cell kinase (Ick) cooperatively acted as ciliary tip-localized IFT turnaround regulators. We also identified that cell cycle-related kinase (Ccrk) is an upstream regulator of Mak/Ick in vivo. Simultaneous disruption of Mak and Ick resulted in severe progressive retinal degeneration in mice. Mak overexpression restored the ciliary defects caused by Ick deficiency in cultured cells. Gene delivery of Ick and pharmacological inhibition of fibroblast growth factor receptors, the negative regulators of Ick, rescued retinal degeneration in retinal ciliopathy model Mak−/− mice. Activation of Mak, Ick, and Ccrk suppressed ciliopathy-related phenotypes caused by cytoplasmic dynein inhibition.
Conclusions :
This study identified a kinase signaling pathway regulating the IFT turnaround that plays an essential role in retinal photoreceptor maintenance and proposes that the modulation of IFT turnaround can be a promising therapeutic treatment for ciliopathies including retinal degenerative diseases.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.