Our long-term goal is to understand the molecular signals that regulate axonal wiring and connectivity of developing neural circuits that control behavior. While recent work has greatly advanced our knowledge of axon guidance molecules, how signaling conveys directionality is poorly understood. The robustness of cell polarity signaling pathways imparting asymmetry across cellular structures may provide a platform within growth cones to detect and respond to guidance cues. Much progress has been made in identifying a number of planar cell polarity (PCP) proteins involved in regulating axon guidance along the anterior-posterior axis of the developing nervous sytem, yet the signaling mechanisms controlling the direction of axon growth, in vivo, are not well understood. Our preliminary data implicate a member of the PCP pathway, ptk7, as a regulator of axon guidance.
In Aim1, we will test the cellular role of Ptk7 in regulating neuronal morphology, using a combination of anatomical and chimeric analysis.
In Aim2, we will establish the structural motifs required for Ptk7 function in axon guidance.
In Aim3, we will investigate the downstream effectors activated by Ptk7 in axon guidance. This work is significant as it would identify Ptk7 as a novel regulator of axon growth in vertebrates for the first time and provide a better understanding of PCP signaling in axon growth that could lead to new ideas for developing preventative or therapeutic agents for PCP-related disease in humans.
In this basic research proposal we will investigate a fundamental problem in the development of a functioning nervous system: how axons navigate to their correct target in order to assemble into circuits that control behavior. This is an important question because disruptions in this process can underlie mental and neurological disorders. The proposed research will lead to new knowledge understanding that could provide the basis for treatment of these neurodevelopmental disorders.
