How do cells regulate the assembly of cilia?

The cilium of a mouse fibroblast cell.  TTBK2::GFP (green) localizes to the transition zone between the centriole (red) and the cilium (magenta) to initiate ciliogenesis and maintain cilia structure

The cilium of a mouse fibroblast cell. TTBK2::GFP (green) localizes to the transition zone between the centriole (red) and the cilium (magenta) to initiate ciliogenesis and maintain cilia structure

Cilia and flagella are tiny, microtubule-based cellular projections that are most widely known for their role in cell motility. Beyond this, non-motile primary are critically linked to embryonic development and a range of human diseases because of their roles in mediating important cellular signaling pathways. These signals control a variety of processes vital for shaping tissues and organs during development, and for maintaining their functions during adulthood.

Despite the clear importance of cilia in human health, we know very little about the mechanisms that control the decision of a cell to assemble or disassemble its cilium. In previous work, we identified the serine-threonine kinase Tau tubulin kinase 2 (TTBK2) as an essential regulator of cilium assembly. In our current work, we are working to identify additional components of this and other pathways that control cilia formation. We are also exploring how ciliary dynamics differ by cell type.

 

 

How do cilia control the development and function of neurons?

In addition to an essential role in initiating cilia formation, the gene encoding TTBK2 is also mutated in a type of inherited human ataxia. This raises the exciting possibility that ciliary defects may be implicated in some adult-onset neurodegenerative conditions. While primary cilia are known to be important in neural development, primarily through their role Hedgehog signaling, the function of cilia in the adult nervous system has not been well defined.

Cilia are required for neural development.  Ventral neural progenitor cells in the developing mouse spinal (red and green) are specified by a gradient of Sonic Hedgehog in wild type embryos (left). In embryos that lack cilia, such as  Ttbk2  mutant embryos (right), these cells are not properly specified or patterned.

Cilia are required for neural development. Ventral neural progenitor cells in the developing mouse spinal (red and green) are specified by a gradient of Sonic Hedgehog in wild type embryos (left). In embryos that lack cilia, such as Ttbk2 mutant embryos (right), these cells are not properly specified or patterned.

Our lab will make use of conditional mouse mutants to examine the requirements for primary cilia as well as for Ttbk2 in the adult brain. We will also examine the roles of Ttbk2 and the closely related kinase Ttbk1 in the development and maintenance of the nervous system.