Loss of ift122, a Retrograde Intraflagellar Transport (IFT) Complex Component, Leads to Slow, Progressive Photoreceptor Degeneration Due to Inefficient Opsin Transport

Abstract

Edited by Velia FowlerIn the retina, aberrant opsin transport from cell bodies to outer segments leads to retinal degenerative diseases such as retinitis pigmentosa. Opsin transport is facilitated by the intraflagellar transport (IFT) system that mediates the bidirectional movement of proteins within cilia. In contrast to functions of the anterograde transport executed by IFT complex B (IFT-B), the precise functions of the retrograde transport mediated by IFT complex A (IFT-A) have not been well studied in photoreceptor cilia. Here, we analyzed developing zebrafish larvae carrying a null mutation in ift122 encoding a component of IFT-A. ift122 mutant larvae show unexpectedly mild phenotypes, compared with those of mutants defective in IFT-B. ift122 mutants exhibit a slow onset of progressive photoreceptor degeneration mainly after 7 days post-fertilization. ift122 mutant larvae also develop cystic kidney but not curly body, both of which are typically observed in various ciliary mutants. ift122 mutants display a loss of cilia in the inner ear hair cells and nasal pit epithelia. Loss of ift122 causes disorganization of outer segment discs. Ectopic accumulation of an IFT-B component, ift88, is observed in the ift122 mutant photoreceptor cilia. In addition, pulsechase experiments using GFP-opsin fusion proteins revealed that ift122 is required for the efficient transport of opsin and the distal elongation of outer segments. These results show that IFT-A is essential for the efficient transport of outer segment proteins, including opsin, and for the survival of retinal photoreceptor cells, rendering the ift122 mutant a unique model for human retinal degenerative diseases.

Intraflagellar Transport Complex A Genes Differentially Regulate Cilium Formation and Transition Zone Gating

“…Finally, our study reveals differential roles for IFT-A proteins in regulating IFT and the structures of distinct cilia subtypes, similar to what has been found for C. elegans kinesin-2 motors [20][21][22][23]. Therefore, our findings go beyond the recent emerging model of strong ciliogenesis roles for the metazoan IFT-A core, but not the IFT-A non-core [9,12,40]. Cell-specific heterogeneity of IFT-A complex organization and function has important implications for mammalian ciliary signal regulation and ciliopathy mechanisms.…”

“…Biochemically organized into core (IFT122/140/144) and noncore (IFT43/121/139) submodules, intraflagellar transport complex A (IFT-A) regulates ciliogenesis, retrograde IFT, and ciliary protein delivery and retrieval [4][5][6][7][8][9][10][11][12]. However, global versus cell-specific roles of individual IFT-A proteins are not well understood, especially in vivo.…”

Alterations in the balance of tubulin glycylation and glutamylation in photoreceptors leads to retinal degeneration

“…The degeneration could be related to a partial dysfunction of the IFT in the connecting cilia, which is considered a possible cause of retinal degeneration (Alfinito and Townes-Anderson, 2002;Boubakri et al, 2016;Bujakowska et al, 2015;Hollingsworth and Gross, 2012;Jiang et al, 2009). Indeed, a number of photoreceptors showed abnormalities in rhodopsin localization in retinas of old Ttll3 −/− mice.…”

The route of the visual receptor rhodopsin along the cilium

“…Mutations in genes encoding the anterograde motor, kinesin-2 (e.g. Marszalek et al, 2000;Lopes et al, 2010), IFT20 (Keady et al, 2011), IFT88 (Pazour et al, 2002), IFT140 (Crouse et al, 2014), IFT122 (Boubakri et al, 2016), IFT57 (Krock and Perkins, 2008), and the BBS proteins, BBS2 (Nishimura et al, 2004), BBS3 (Zhang et al, 2011), BBS4 (Abd-El- Barr et al, 2007), BBS6/MKKS (Ross et al, 2005) and BBS8 (Hsu et al, 2017;Dilan et al, 2018) have all been shown to affect RHO delivery, outer segment formation and maintenance, and typically result in photoreceptor degeneration.…”