Define the pathways that control cilium initiation

  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

Primary cilia are tiny, microtubule-based cellular projections. Once thought to be vestigial, surprising findings over the past decade have shown that cilia play an essential role in mediating a critical cell signaling pathway: the Hedgehog pathway. Correct levels of Hedgehog signaling are vital during embryonic development and is also important in adults where the pathway is implicated in tissue homeostasis and repair as well as in cancer.  The importance in human health is further underscored by findings linking defects in ciliary structure and function to a set of human genetic disorders, now collectively known as ciliopathies. 

Despite the clear importance of primary cilia in human health,  we know little about the mechanisms that control the decision of a cell to assemble or disassemble the cilium. In previous work, we identified the serine-threonine kinase Tau tubulin kinase 2 (TTBK2) as an essential regulator of cilium initiation downstream of cell cycle factors. In our current work, we are working to identify additional components of this and pathways that control cilia formation, as well as exploring how cilium regulation may differ by cell type.

 

 

Investigate the roles of primary cilia in the developing and adult nervous system

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.