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.

• Authors: Sarah C Goetz, Karel F Liem Jr, Kathryn V Anderson
• Journal: Cell (Cell) Vol. 151 Issue 4 Pg. 847-858 (Nov 09 2012) ISSN: 1097-4172 [Electronic] United States
• PMID: 23141541 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Cell Cycle Proteins
• Hedgehog Proteins
• Microtubule-Associated Proteins
• tau-tubulin kinase
• Protein Serine-Threonine Kinases

Topics

• Animals
• Cell Cycle Proteins (metabolism)
• Cilia (metabolism)
• Hedgehog Proteins (metabolism)
• Humans
• Mice
• Microtubule-Associated Proteins (metabolism)
• Mutation
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Signal Transduction
• Spinocerebellar Ataxias (metabolism)