Patterning dendritic branches with environmental and neuronal surface molecules

Stanford University, Stanford CA

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Abstract

During neuronal development, stereotyped axonal and dendritic arbor shapes are often achieved through dynamic and stochastic growth, branching and retraction. The shape of arbors are also determined by guidance receptors and ligands. How guidance receptor and ligands interact to achieve the proper shape through a dynamic process is unknown. Our previous work funded by this grant identified that extracellular ligand SAX-7/LICAM dictates the shape of the PVD sensory neuron through its binding to the dendritic guidance receptor DMA-1. Our current unpublished results argue against the popular view in the field and support a new model. Unexpectedly, we find that ligand-free DMA-1 is sufficient to promote robust, stochastic dendrite growth. Our data also suggest that ligand binding might inhibit growth, prevents retraction, and specifies arbor shape. We propose that DMA-1 needs to be endocytosed and subsequently reinserted onto the plasma membrane via recycling endosomes, to generate a pool of ligand-free DMA-1 which is critical to promote dendritic growth. Therefore, ligand-free guidance receptor mediates intrinsic, stochastic dendritic growth, while extracellular ligands instruct dendrite shape by inhibiting growth. Specifically, I propose to test this new model of how ligand-receptor interactions mediate the dynamic process of dendrite development characterized by stochastic growth and retraction but ultimately gives rise to arbors with stereotyped shape with three aims. In Aim 1, we will design specific experiments to dissect the function of the ligand free DMA-1 and ligand bound DMA-1. In Aim 2, we will understand how the cell biology of dendrite guidance receptor is regulated to achieve its function. The size of the dendrite is also determined by its interaction with a neighboring neuron’s dendritic arbor. In Aim 3, we will understand the molecular mechanisms of dendritic tiling by identify the morphogenetic factor and the dendrite-dendrite interaction that limits the size of PVD dendrite. In summary, this proposal will systematically address the molecular and cell biological mechanisms that specify the dendritic arbors.