Failure of centrosome migration causes a loss of motile cilia in talpid³ mutants

Abstract

*Background: Loss of function mutations in the centrosomal protein TALPID3 (KIAA0586) cause a failure of primary cilia formation in animal models and are associated with defective Hedgehog signalling. It is unclear, however, if TALPID3 is required only for primary cilia formation or if it is essential for all ciliogenesis, including that of motile cilia in multiciliate cells. Results: FOXJ1, a key regulator of multiciliate cell fate, is expressed in the dorsal neuroectoderm of the chicken forebrain and hindbrain at stage 20HH, in areas that will give rise to choroid plexuses in both wt and talpid 3 embryos. Wt ependymal cells of the prosencephalic choroid plexuses subsequently transition from exhibiting single short cilia to multiple long motile cilia at 29HH (E8). Primary cilia and long motile cilia were only rarely observed on talpid 3 ependymal cells. Electron microscopy determined that talpid 3 ependymal cells do develop multiple centrosomes in accordance with FOXJ1 expression, but these fail to migrate to the apical surface of ependymal cells although axoneme formation was sometimes observed. Conclusions: TALPID3, which normally localises to the proximal centrosome, is essential for centrosomal migration prior to ciliogenesis but is not directly required for de novo centriologenesis, multiciliated fate, or axoneme formation. Developmental Dynamics 242:923-931,

Mutations in human homologue of chickentalpid3gene (KIAA0586) cause a hybrid ciliopathy with overlapping features of Jeune and Joubert syndromes

“…KIAA0586 assembles a ring-like structure at the extreme distal end of centrioles. Ablation of TALPID3 results in an aberrant distribution of centriolar satellites involved in protein trafficking to centrosomes; it also causes ciliary vesicle formation reminiscent of loss of Cep290, another CP110-associated protein that is mutated in various human ciliopathies19 20 and leads to failure of centrosome migration 20. A similar failure of centrosome positioning and/or docking is seen in cells lacking function in other genes encoding basal body proteins, including OFD1 (oral-facialdigital syndrome 1)21 and MKS1 (Meckel syndrome 1) 22…”

Cilia in vertebrate left–right patterning

“…In the chicken embryo, Hensen's node is site of the first asymmetric gene expression, but this structure is thought to lack motile cilia. Chicken Talpid3 mutants with cilia defects develop normal LR asymmetry [78][79][80], indicating a cilia-independent mechanism is used for breaking symmetry. Indeed, cell-tracking experiments revealed that asymmetric cell movements around Hensen's node set up asymmetric signalling in the chicken embryo [81].…”

Utilizing the chicken as an animal model for human craniofacial ciliopathies

“…The ta 3 body axis is shortened (Stephen et al, 2015), the lungs are hypoplastic and the liver is fibrotic and cholestatic (Davey et al, 2014). Skeletogenesis is aberrant (Macrae et al, 2010), embryos exhibit unusual vascular abnormalities (Davey et al, 2007) and development and differentiation of the central nervous system is impaired (Buxton et al, 2004; Stephen et al, 2013). With respect to craniofacial abnormalities, ta 3 embryos exhibit a holoprosencephalic-like phenotype: apposition of the eyes at the ventral midline (hypotelorism) with the reduction and anterior displacement of the FNP (Ede and Kelly, 1964a; Ede and Kelly, 1964b).…”

“…The KIAA0586 protein, eventually named TALPID3, was isolated in an early centrosomal proteome analysis (Andersen et al, 2003) and was confirmed to be a centrosomal protein (Yin et al, 2009) that normally localized in a ring at the distal end of the basal body (Kobayashi et al, 2014). The TALPID3 protein was shown to be required for docking of the basal body to the cell surface (Yin et al, 2009) prior to ciliogenesis (Kobayashi et al, 2014) and has also been implicated in centrosome migration (Stephen et al, 2013), control of centrosome length (Stephen et al, 2015) and formation of centriolar satellites (Kobayashi et al, 2014). Loss of the TALPID3 protein, in various model species, resulted in a loss of cilia (Bangs et al, 2011; Ben et al, 2011; Yin et al, 2009), both non-motile and motile (Stephen et al, 2013).…”