Grant: Project Grant

Primary cilia are hair-like, signaling antenna protruding from the cell body on virtually all cell types, including neurons. In the past decade, primary cilia have sparked enormous interest due to the discoveries that mutations in over 100 genes that encode ciliary proteins can lead to 30+ human rare disorders collectively termed "ciliopathies". The brain is particularly vulnerable to impaired primary cilia as reflected in a large group of ciliopathies that are characterized by severe axonal defects associated with intellectual disabilities and autism spectrum disorder. However, we know little of how primary cilia function in the brain. Using our ciliopathies disease models and cilia-specific experimental tools, we are uniquely poised to systematically investigate the primary cilia-dependent mechanisms in axonal development. We recently made exciting progress: We found that impaired cilia in neurons result in malformations of major axon tracts such as corticospinal tract (the longest) and corpus callosum (the biggest). Mutant neurons show defects in axonal growth and guidance, as well as dysregulated cilia-PI3K (Phosphoinositide 3-kinase) signaling. These data are important in beginning to unravel the undefined signaling mechanism linking primary cilia to the control of axonal development. Based on our preliminary work, we will test the intriguing notion that primary cilia function as essential signaling centers to convey environmental signals to neurons for axonal development and circuit formation.