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

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The neurons or nerve cells have slender projections called axons that typically conduct electrical impulses away from the neuron's cell body. These axons need to locate and recognize their appropriate partners for correct wiring of the nervous system. To help them find their way in the developing embryo, axons are tipped with a highly motile and sensitive structure called the growth cone. While a large group of molecules that guide these growth cones have been identified, the signaling molecular pathways mediating this process remain largely unknown. Recent studies have implicated an important role for a pathway called planar cell polarity (PCP) pathway in axon guidance. PCP is the process by which cells become polarized in the plane of a tissue and is important for many developmental processes including neurulation. All epithelial cells exhibit another form of polarity called apical-basal (A-B) polarity that is important for their fundamental function. One of the protein complexes that regulate A-B polarity is called the Scrib complex and is composed of 3 proteins, Scribble (Scrib), Discs Large (Dlg) and Lethal giant larvae (Lgl). Recent studies have demonstrated molecular interactions between PCP and A-B polarity pathway suggesting common functions during embryonic development. We propose to investigate if the Scrib Complex provides an essential molecular link between the PCP pathway and A-B polarity in axon guidance in the developing spinal cord and brain. We will first study the expression pattern of each of Scrib, Dlg and Lgl in the developing brain and spinal cord and compare these patterns to those of 3 PCP genes called Vangl2, Frizzled3 and Celsr3. Next, we will knockdown the expression of each of Scrib, Dlg and Lgl in spinal cord preparations and brain cultures from wild-type and from mice mutant for the PCP gene Vangl2 and we will use various labeling approaches to investigate any resulting defect in axon guidance. Our study will provide important insights into the signaling pathways involved in axon guidance that are essential for proper wiring of the central nervous system.