Primary Cilia: Vital Cellular Signaling Hubs
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, antenna-like cellular projections. Historically, these structures were best known for their role in cell motility, while non-motile primary cilia were overlooked by cell biologists. However, recent work has uncovered exciting and unexpected links between primary cilia and core signaling pathways that control a variety of developmental processes, and maintain tissues during adulthood.
Our lab explores fundamental questions about these fascinating organelles and their roles in human health. In particular, we are interested in understanding the requirements for cilia in the developing and adult nervous system. We are also working to define the mechanisms that control the decision of a cell to assemble or disassemble its cilium.
How do cilia control the development and function of neurons?
Cilia are required for brain development. Dysfunction of primary cilia is linked to numerous genetic disorders in humans (“ciliopathies”). Many of these are associated with a host of neurological deficits that range from physical brain defects to autism-spectrum like disorders and cognitive impairment. In addition to regulating brain development, our lab has demonstrated that cilia are required to maintain the function and viability of specific neurons within the brain: Purkinje neurons of the cerebellum (below).
Cilia are required to maintain neuronal viability. Purkinje neurons (red) in the cerebellum are lost in patches (arrowhead) in mice in which the cilium assembly kinase TTBK2 is conditionally deleted during adulthood. Tissue sections shown are from animals 5 months following loss of TTBK2 and cilia.
Our current work is focused on defining the ciliary signals that mediate the viability of neurons in the cerebellum, and in other brain regions affected by human neurodegenerative conditions. We are also exploring the roles of cilia in the development of the cerebellum.
How is cilium assembly regulated?
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 a kinase that is an essential regulator of cilium assembly. Our current work uses state-of-the-art proteomics and imaging approaches identify additional players that control the assembly of these critical signaling hubs.