Molecular crosstalk between apical-basal polarity and planar cell polarity in axon guidance

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Neurons are highly polarized cells with structurally and functionally distinct compartments called axons and dendrites. Various axons called commissural axons interconnect the two halves of the central nervous system during embryonic and early postnatal developmental periods for proper integration and coordination of left-right neuronal activities. To guide these axons in their projections, they are tipped with highly motile and sensitive structures called the growth cones that perceive gradients of guidance cues and can be either attracted towards the source or repulsed away from it. Many guidance molecules have been identified; however, how these molecules signal to provide directional control of axon growth is still largely unknown. An increasing amount of evidence has implicated a signaling pathway called planar cell polarity (PCP) signaling in mediating this process. PCP is the process by which cells become polarized in the plane of an epithelium. It includes a group of essential genes including Frizzled (Fz) and Vangl. Mutations in these genes cause defects in neural tube formation and in commissural axon guidance. It was suggested that, in addition to PCP signaling, navigating growth cones might rely on more sensitive mechanisms implicating another kind of polarity called the apical-basal polarity pathway (ABP). ABP controls polarity within the epithelial cells and is mediated by many genes including Par3, Par6 and Scribble1 (Scrib1). The latter physically and genetically interacts with the PCP gene Vangl2 during neural tube formation. Our project aims at dissecting the molecular link between the ABP gene Scrib1 and the PCP gene Vangl2 during commissural axon guidance. We will investigate interactions between these two genes in mediating commissural axon guidance of the developing spinal cord and forebrain. We will next determine whether knockdown of Scrib1 or Vangl2 or Par3 in neuronal cultures and slices will affect neuronal polarity, PCP-mediated axonal growth in culture and subcellular localization of various ABP and PCP markers. We will also identify the downstream effectors of Scrib1 that act directly on the growth cone, changing its structure in response to guidance cues.****Commissural axon guidance in the developing spinal cord and brain remains an intriguing phenomenon. Our study will provide important insights into this fundamental developmental process and will help dissecting the role of the ABP gene Scrib1 and PCP signaling in mediating this process.************