Cell type‐specific regulation of ciliary transition zone assembly in vertebrates

• Published in: The EMBO journal Vol. 37; no. 10
• Main Authors: Wiegering, Antonia, Dildrop, Renate, Kalfhues, Lisa, Spychala, André, Kuschel, Stefanie, Lier, Johanna Maria, Zobel, Thomas, Dahmen, Stefanie, Leu, Tristan, Struchtrup, Andreas, Legendre, Flora, Vesque, Christine, Schneider‐Maunoury, Sylvie, Saunier, Sophie, Rüther, Ulrich, Gerhardt, Christoph
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.05.2018; Springer Nature B.V; EMBO Press; John Wiley and Sons Inc
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adaptor Proteins, Signal Transducing - physiology; Animals; Assembly; Caenorhabditis elegans; Carrier Proteins - physiology; Cell Membrane Structures; Cells, Cultured; Cilia; Cilia - physiology; ciliopathies; Complexity; EMBO05; Embryo, Mammalian - cytology; Embryo, Mammalian - metabolism; Embryos; Fibroblasts - cytology; Fibroblasts - metabolism; HEK293 Cells; Humans; Immunofluorescence; Invertebrates; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Modules; Mutation; Nematodes; Nphp; Nuclear Proteins - physiology; Proteins; Proteins - physiology; Rpgrip1; Rpgrip1l; Transcription Factors - physiology; Vertebrates; cilia; ciliopathies; Rpgrip1l; Nphp; Rpgrip1
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.201797791

Ciliopathies are life‐threatening human diseases caused by defective cilia. They can often be traced back to mutations of genes encoding transition zone (TZ) proteins demonstrating that the understanding of TZ organisation is of paramount importance. The TZ consists of multimeric protein modules that are subject to a stringent assembly hierarchy. Previous reports place Rpgrip1l at the top of the TZ assembly hierarchy in Caenorhabditis elegans . By performing quantitative immunofluorescence studies in RPGRIP1L −/− mouse embryos and human embryonic cells, we recognise a different situation in vertebrates in which Rpgrip1l deficiency affects TZ assembly in a cell type‐specific manner. In cell types in which the loss of Rpgrip1l alone does not affect all modules, additional truncation or removal of vertebrate‐specific Rpgrip1 results in an impairment of all modules. Consequently, Rpgrip1l and Rpgrip1 synergistically ensure the TZ composition in several vertebrate cell types, revealing a higher complexity of TZ assembly in vertebrates than in invertebrates. Synopsis The transition zone (TZ) compartment within the cilium controls the ciliary entry and exit of proteins, and its disruption is linked to dysfunctional cilia and ciliopathies. Analyses in various mouse and human cell types reveal a higher complexity of TZ assembly in vertebrates as compared to the simpler hierarchy known from Caenorhabditis elegans . A Rpgrip1l‐Cep290‐Nphp4‐Invs‐Nphp1 axis defines the hierarchy of TZ assembly in mice. Assembly of a functional TZ depends on sequential recruitment of TZ proteins in appropriate amounts. Rpgrip1l and Rpgrip1 synergistically ensure proper TZ assembly in a cell type‐specific manner. Graphical Abstract Synergistic roles of paralogous proteins Rpgrip1 and Rpgrip1l suggest a higher complexity of ciliary transition zone assembly in mouse embryos and human embryonic cells as compared to the simpler hierarchy known from invertebrates.