Identifying regulatory networks that govern primary cilia remodeling and neural signaling

Project Summary/Abstract Primary cilia are sensory organelles of a few microns that are present on most vertebrate cells. They convert surrounding cues into intracellular signals that are critical for cellular functions. The cilium concentrates key regulators of the Sonic Hedgehog pathway and a wide range of versatile classes of molecules, including G protein-coupled receptors and second messengers. Despite the clear importance of cilia during embryonic development and the homeostasis of many tissues and organs, the mechanisms that govern the regulation of cilia themselves remain unclear. Primary cilia dysfunction causes a variety of developmental syndromes with neurological defects and cognitive impairment. Even though most neurons have a primary cilium, it is still unknown how this organelle modulates neuron morphology and connectivity. The long-term goals of my research group are to i) discover novel mechanisms and processes that govern cilium biogenesis, ii) define the fundamentals of how and why the cilium dynamically remodels itself, and iii) uncover the underexplored roles of neuronal cilia in the brain. In the absence of such knowledge, identifying potential tractable modifiers of cilia regulation will remain difficult, particularly in the brain. We employ an interdisciplinary approach using unbiased screening strategies, mouse models, cutting-edge microscopy, and cell and molecular biology. The advancements made over the last five years have been critical in identifying novel molecular foundations of primary cilia dynamics and ciliary composition in neurons. We will keep building on these first steps to help advance therapeutic strategies targeting perturbed ciliary pathways.