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Restricted Access: the Transition Zone Controls Ciliary Composition and Signaling
Author(s) -
Reiter Jeremy
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.78.2
Subject(s) - ciliogenesis , cilium , ciliopathy , biology , microbiology and biotechnology , intraflagellar transport , basal body , smoothened , signal transduction , ciliopathies , hedgehog signaling pathway , bardet–biedl syndrome , mutant , genetics , flagellum , gene , phenotype
Cilia and vertebrate Hh signaling are intimately related. Mutations that affect ciliogenesis abrogate Hh signaling, and components of the Hh signal transduction pathway function at cilia. One component of the Hh signal transduction pathway, Smoothened (Smo), moves to cilia in response to Hh signals. In investigating how Smo moves to cilia, we identified a complex of proteins that form part of the transition zone, a region at the base of the cilium. This complex includes the three members of the Tectonic family, extracytosolic glycoproteins that interact with transmembrane components of the transition zone such as Tmem231. Homozygous mouse Tmem231 mutants show defects in ciliogenesis in some tissues, such as the neural tube, with preservation of cilia in other tissues, such as the kidney, biliary tract and limb buds. In tissues in which Tmem231 is dispensible for ciliogenesis, Tmem231 is critical for the ciliary localization of membrane associated proteins such as Smo. Consistent with the hypothesis that the control of ciliary composition is critical for signaling, Tmem231 mutants display developmental defects including polydactyly and cystic kidneys. Within ciliated cells, Tmem231 is required for formation of the MKS complex at the transition zone, but is dispensable for the formation of the Nephronophthisis‐associated transition zone complex. Mutations in human TMEM231 cause Meckel syndrome, a perinatal lethal disorder characterized by heterotaxia, polydactyly and cystic kidneys, and a form of Orofaciodigital syndrome, another ciliopathy. Therefore, Tmem231 is critical for the assembly of the transition zone MKS complex that regulates the composition of the ciliary membrane and thus the signaling properties of cilia. In addition to Smo, other ciliary transmembrane proteins such as Pkd2, mutated in autosomal dominant polycystic kidney disease, depend on the transition zone to localize to cilia. As predicted from loss of ciliary Pkd2, mouse transition zone mutations develop kidney cysts. By using superresolution imaging and innovative genetic tools, we have begun to dissect how the transition zone regulates the localization of membrane proteins such as Smo and Pkd2 to cilia and controls their activity.