Mouse models of FAM161A-associated RP28 have revealed structural defects in the CC, with spread MTDs and disturbed membrane disc organization that underlie photoreceptor loss. Mutations in the gene that encodes the microtubule-binding protein FAM161A, which localizes at the CC, have been associated with the human pathology retinitis pigmentosa 28 (RP28), a subtype of retinitis pigmentosa, the most prevalent human inherited retinal disease with an incidence of 1/4,000 worldwide. This structural linker, emanating from a mature centriole, is made of 9 microtubule doublets (MTDs) that extend distally to form the axonemal stalk, the basis of the OS onto which hundreds of stacked membrane discs that contain phototransduction proteins are positioned. These highly specialized ciliated cells are partitioned into 2 main regions, a photosensitive outer segment (OS) and a photoreceptor inner segment, which are connected via a thin bridging structure known as the connecting cilium (CC) with its underlying ciliary basal body. The retina is a thin tissue lining the back of the eyeball that contains photoreceptor cells, which convert light inputs into electrical signals, a process crucial for the detection of visual stimuli. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: Authors declare no competing interests. and the Novartis Foundation for medical-biological Research (18B112) attributed to P.G. and C.K., the Fondation Asile des Aveugles (fonds RO1011) attributed to Y.A., European Commission SEC-2009-4.3-02 (project 242361) attributed to C.M., the EMBO fellowship (ALTF-284-2019) to E.B. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All data are available in the main text or the supplementary information.įunding: This work is supported by the ERC StG 715289 (ACCENT), the Swiss National Foundation (SNSF) PP00P3_187198 attributed to P.G., the Pro Visu Foundation attributed to P.G, V.H. Received: FebruAccepted: ApPublished: June 16, 2022Ĭopyright: © 2022 Mercey et al. PLoS Biol 20(6):Īcademic Editor: Renata Basto, Institut Curie, FRANCE (2022) The connecting cilium inner scaffold provides a structural foundation that protects against retinal degeneration. Furthermore, we show that Fam161a disruption in mouse leads to specific CC inner scaffold loss and triggers microtubule doublet spreading, prior to outer segment collapse and photoreceptor degeneration, suggesting a molecular mechanism for a subtype of retinitis pigmentosa.Ĭitation: Mercey O, Kostic C, Bertiaux E, Giroud A, Sadian Y, Gaboriau DCA, et al. Dissecting CC inner scaffold assembly during photoreceptor development in mouse revealed that it acts as a structural zipper, progressively bridging microtubule doublets and straightening the CC. ![]() Here, using expansion microscopy and electron microscopy, we reveal the molecular architecture of the CC and demonstrate that microtubules are linked together by a CC inner scaffold containing POC5, CENTRIN, and FAM161A. While structural defects of the CC have been associated with retinal degeneration, its nanoscale molecular composition, assembly, and function are barely known. These cells possess a photosensitive outer segment linked to the cell body through the connecting cilium (CC). Inherited retinal degeneration due to loss of photoreceptor cells is a leading cause of human blindness.
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