Abstract
ABSTRACTDefects in cilia centrosomal genes cause pleiotropic clinical phenotypes, collectively called ciliopathies. Cilia biogenesis is initiated by the interaction of positive and negative regulators. Centriolar coiled coil protein 110 (CP110) caps the distal end of the mother centriole and is known to act as a suppressor to control the timing of ciliogenesis. Here, we demonstrate that CP110 promotes cilia formation in vivo, in contrast to findings in cultured cells. Cp110−/− mice die shortly after birth owing to organogenesis defects as in ciliopathies. Shh signaling is impaired in null embryos and primary cilia are reduced in multiple tissues. We show that CP110 is required for anchoring of basal bodies to the membrane during cilia formation. CP110 loss resulted in an abnormal distribution of core components of subdistal appendages (SDAs) and of recycling endosomes, which may be associated with premature extension of axonemal microtubules. Our data implicate CP110 in SDA assembly and ciliary vesicle docking, two requisite early steps in cilia formation. We suggest that CP110 has unique context-dependent functions, acting as both a suppressor and a promoter of ciliogenesis.
Highlights
The primary cilium is a near ubiquitous microtubule (MT)-based organelle that protrudes from the cell surface of most vertebrate cells
Organogenesis defects in mice with complete loss of coil protein 110 (CP110) The mouse Cp110 (Ccp110) gene contains 16 exons and encodes five different transcripts, the longest of which is translated into a protein of 1004 amino acid residues
We carried out standard homologous recombination in mouse embryonic stem cells (ESCs) and selected positive clones after neomycin treatment and validation by long-range PCR
Summary
The primary cilium is a near ubiquitous microtubule (MT)-based organelle that protrudes from the cell surface of most vertebrate cells. Impaired cilia biogenesis and/or function impact the development of multiple organs resulting in pleiotropic phenotypes, collectively termed ciliopathies (Hildebrandt et al, 2011; Nigg and Raff, 2009; Novarino et al, 2011). These phenotypes can include retinal degeneration, cognitive impairment, neural tube defects, hydrocephalus, polycystic kidneys, polydactyly, situs inversus and obesity. Depending on the combination of defects, ciliopathies can be categorized clinically as distinct disorders, such as Bardet–Biedl. The observed clinical diversity in ciliopathies might reflect a cumulative genetic load of variants/mutations and interactions among cilia centrosome-associated genes (Novarino et al, 2011; Sang et al, 2011; Zaghloul and Katsanis, 2010)
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