The Spinocerebellar Ataxia-Associated Gene Tau Tubulin Kinase 2 Controls the Initiation of Ciliogenesis

Abstract

The primary cilium has critical roles in human development and disease, but the mechanisms that regulate ciliogenesis are not understood. Here we show that Tau tubulin kinase 2 (TTBK2) is a dedicated regulator of the initiation of ciliogenesis in vivo. We identified a null allele of mouse Ttbk2 based on loss of Sonic hedgehog activity, a signaling pathway that requires the primary cilium. Despite a normal basal body template, Ttbk2 mutants lack cilia. TTBK2 acts at the distal end of the basal body, where it promotes the removal of CP110, which caps the mother centriole, and promotes recruitment of IFT proteins, which build the ciliary axoneme. Dominant truncating mutations in human TTBK2 cause Spinocerebellar Ataxia type 11 (SCA11); these mutant proteins do not promote ciliogenesis and inhibit ciliogenesis in wild-type cells. We propose that cell cycle regulators target TTBK2 to the basal body, where it modifies specific targets to initiate ciliogenesis.

Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes

“…TTBK2 recruitment to the centrosomal area and CP110 cap removal from the mother centriole are known to occur at the beginning of ciliogenesis (11,17). Both TTBK2 recruitment and CP110 removal appeared normal in CEP290 null cells (Supplemental Figure 5).…”

C2cd3 is critical for centriolar distal appendage assembly and ciliary vesicle docking in mammals

“…MEFs were established using a previously published protocol (24) and were immortalized by stably expressing SV40 Large T Antigen (a gift from Baolin Wang, Cornell University, (9,10) suggests that C2cd3 is critical for the assembly of centriolar distal appendages, which in turn underlie the recruitment of Ttbk2, Ift88, and Ift52 as well as the removal of Cp110 and the docking of ciliary vesicles. C2cd3 may play a more direct role in recruiting Ift88 to the distal appendages.…”

“…Distal appendages are critical for the recruitment of Tau tubulin kinase 2 (Ttbk2), which appears to play a critical role in removing centrosomal protein of 110kD (Cp110, also known as Ccp110, Mouse Genome Informatics, www.informatics. jax.org/marker/MGI:2141942), an inhibitor of ciliogenesis, from the distal end of the mother centriole (10). Recent studies have also suggested that components of the distal appendages are essential for docking ciliary vesicles to the mother centriole (9,(11)(12)(13)(14).…”

The Centrosome and Its Duplication Cycle

“…7). This is promoted by Tau-tubulin kinase 2 (TTBK2); in TTBK2 null mouse embryo, E10.5 neural cilia are missing in 10.5-day-old embryos, and yet basal bodies dock to the cell cortex (Goetz et al 2012). Cep83 appears to be upstream of this process because its depletion blocks centrosome-to-membrane association, and the undocked centrioles fail either to recruit TTBK2 or release CP110 .…”