Neuronal primary cilium: a centralized signaling node for dendrite morphogenesis

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The appropriate size and shape of neuronal dendritic arbors is a key determinant of how neurons receive, integrate, and encode circuit information. We recently made an unexpected finding that the neuronal primary cilium, a remarkably short (just a few m long), singular signaling antenna that protrudes from the neuronal soma, is a centralized signaling node that robustly influences dendrite morphology. The goal of this NSERC DG Research Program is to define the role of the neuronal primary cilium in neuronal morphogenesis and connectivity. ******The neuronal primary cilium possesses a diverse cast of signaling components to act as a signaling hub and relay of environmental signals to the soma for major cell functions. However, due to a lack of methods to precisely control cilia-specific signaling events, the exact role of ciliary signaling in overall brain development and function remains enigmatic. My work has overcome this technical limitation and established an experimental framework to interrogate ciliary signaling in developing neurons, which we will fully exploit in this new NSERC project. ******In preliminary work, we used a mouse model mutant for Arl13b, a ciliary-specific small GTPase critical for ciliary signal transduction. We found that disruption of ciliary signaling in pyramidal neurons significantly impairs dendritic arborization in the cerebral cortex. This proposal addresses a key question: How does primary ciliary signaling exert such profound effects on dendrite morphogenesis? In three aims, we will: ******Aim 1. To characterize the altered dendritic arbor growth and patterning in Arl13b mutant cortical neurons. High-resolution confocal microscopy will be performed for a detailed characterization of the dendritic morphology. Time-lapse live imaging will be performed to analyze the dendritic arbor growth dynamics.******Aim 2. To delineate the ciliary-driven intracellular signaling mechanisms in dendrite morphogenesis. We will test the hypothesis that the ciliary-PI3K (Phosphoinositide 3-kinase) signaling plays a central role in modulating dendrite development. We will generate novel optogenetic tools to dissect how ciliary-PI3K signaling cascades govern dendritic growth dynamics and morphology. ******Aim 3. To define the ciliary signaling receptors that modulate dendrite morphogenesis. We will focus on the ciliary receptors known to influence dendrite morphology and mislocalized in Arl13b mutant cilia for this aim. Optogenetically induced ciliary receptor activation will be used to directly examine these receptors' influence on dendrite morphology development. ******Each aim is specifically designed to provide HQP with diverse training in neurodevelopment, molecular genetics, and novel experimental tool development and implementation. Upon completion of these aims, we will have gained transformative mechanistic insights into how neuronal cilia function in the developing brain at a level never before achieved. *****