Abstract
Cilia formation and function require a special set of trafficking machinery termed intraflagellar transport (IFT), consisting mainly of protein complexes IFT-A, IFT-B, BBSome, and microtubule-dependent molecular motors. Tetratricopeptide repeat-containing (TTC) proteins are widely involved in protein complex formation. Nine of them are known to serve as components of the IFT or BBSome complexes. How many TTC proteins are cilia-related and how they function, however, remain unclear. Here we show that twenty TTC genes were upregulated by at least 2-fold during the differentiation of cultured mouse tracheal epithelial cells (MTECs) into multiciliated cells. Our systematic screen in zebrafish identified four novel TTC genes, ttc4, -9c, -36, and -39c, that are critical for cilia formation and motility. Accordingly, their zebrafish morphants displayed typical ciliopathy-related phenotypes, including curved body, abnormal otolith, hydrocephalus, and defective left-right patterning. The morphants of ttc4 and ttc25, a known cilia-related gene, additionally showed pronephric cyst formation. Immunoprecipitation indicated associations of TTC4, -9c, -25, -36, and -39c with components or entire complexes of IFT-A, IFT-B, or BBSome, implying their participations in IFT or IFT-related activities. Our results provide a global view for the relationship between TTC proteins and cilia.
Highlights
Cilia are evolutionarily conserved, microtubule-based, hair-like organelles present in most animal cells
Following the establishment of an air-liquid interface (ALI), mouse tracheal epithelial cells (MTECs) cultured in vitro simultaneously generate hundreds of centrioles, which serve as the basal bodies of cilia, followed by the formation of dense motile cilia (Fig 1A) [23,29]
We have demonstrated that during MTEC differentiation the centriole amplification peaks at ALI day 3 (d3) and multiciliation reaches plateau at around ALI d5 [24,29]
Summary
Microtubule-based, hair-like organelles present in most animal cells. They play important roles in cell movement, environment sensing, and signal transduction [1,2,3]. Defects in cilia assembly and function result in severe disorders called ciliopathies, including infertility, retinal degeneration, hydrocephalus, polycystic kidney, and situs inversus [2,4,5]. It is important to elucidate the mechanisms underlying ciliogenesis and ciliary functions for the understanding and the treatment of ciliopathies.
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