Book Description

Dendrite morphogenesis is a critical developmental process that establishes the architecture and function of neural circuits. Outgrowing neurites are guided by a variety of extracellular cues that are recognized by guidance receptors on the surface of the cell, which in turn modulate intracellular signaling pathways and cytoskeletal regulators to mediate changes in cell morphology. The regulation of these guidance receptors allows for correct pathfinding and efficient outgrowth. However, the precise mechanisms linking guidance receptor-ligand interactions to changes in the cytoskeleton, and their regulation, are not fully understood. Using the highly branched dendritic arbor of the PVD neuron in C. elegans as a model system, we identified a proteolytic cleavage event that regulates guidance receptor localization to promote dendrite outgrowth. We showed that the Furin homolog KPC-1 cleaves the co-receptor HPO-30, previously shown to form a complex with the guidance receptor DMA-1. This cleavage event is necessary for formation of higher order dendrites in PVD. Furthermore, we show that this cleavage event promotes the internalization of DMA-1 from the plasma membrane into RAB-10-positive recycling endosomes, and that excess DMA-1 on the membrane is associated with overstabilization of dendrites and reduced outgrowth. Our work reveals a mechanism by which guidance receptor localization is controlled in order to promote dendrite outgrowth. In addition, during development, neurons must coordinate various cytoskeletal regulators that work together to create structured actin networks during dendrite morphogenesis. Here, we showed that outgrowth of the PVD neuron occurs through localized expansions in the dendrite (termed "swellings") at branch initiation sites, followed by the rapid extension of thin filopodia from these swelling sites. The formation of filopodia required UNC-115/abLIM, an actin-binding LIM protein, and UNC-34/Ena/VASP, which promotes the extension of linear actin bundles. On the other hand, the formation of both swellings and filopodia depends on the WAVE Regulatory Complex (WRC), which promotes the formation of branched actin networks. We therefore propose that, following guidance receptor activation, WRC creates local branched actin networks at swellings that stochastically specify sites of new dendritic branches. UNC-34 and UNC-115 are then recruited to bundle actin filaments and create filopodia that initiate these new dendritic branches. In summary, dendrite morphogenesis requires regulation of guidance receptors and their down-stream signaling pathways. We have identified a co-receptor cleavage event that regulates guidance receptor localization to allow both dendrite outgrowth and stabilization, as well as a mechanism that coordinates cytoskeletal changes downstream of guidance receptor signaling.