Dendrite development, function, degeneration and regeneration - Project Summary/Abstract Since 2002, a major focus of our lab has been dendrite development. Dendrite arborization patterns are critical components of neural circuits; they influence the synaptic or sensory inputs a neuron receives. Back in 2002, little was known about the molecular mechanisms that control dendrite development. To use Drosophila genetics to identify core programs that control dendrite development, we first showed that the larval dendritic arborization (da) neurons, a group of sensory neurons, are well suited for this purpose. They can be divided into four classes based on their class-specific dendritic morphology. By using this system, we have identified and studied many genes that control neuronal type specific dendritic morphology, the size of dendritic arbor, and how different neurons organize their dendrites relative to one another. Many of the molecular mechanisms that control dendrite development originally discovered in Drosophila are conserved in mammals. Given that dendrite defects are associated with neurological disorders such as Down’s syndrome and a subset of autism spectrum disorder, elucidating molecular mechanisms that control dendrite development is not only important in basic neuroscience but also could contribute to potential future treatments of neurological disorders. Building on our previous findings, we continue to explore three related research areas: (1) Elucidating the mechanisms that control dendrite development. We are keen to identify the tiling signal that mediates the mutual repulsion of the dendrites of adjacent c4da neurons, so the dendrites of those neurons form a regular array without overlap. We are using the cell surface proximity labeling technique developed by our collaborator Dr. Jiefu Li to characterize cell surface proteomes of da neurons to identify the tiling signal. (2) Studying mechano-sensation exhibited by Drosophila da neurons. All da neurons are mechano-sensitive (MS), prompting us to ask how MS channels work: (a) The gating mechanism of NOMPC. We have demonstrated that NOMPC is a bona fide MS channel with its 29 Ankyrin repeats (ARs) and the pre-S1 linker acting as tethers that convey forces from microtubules to gate the channel. We are collaborating with Dr. Yongli Zhang and Dr. Yifan Cheng to use optic tweezers and cryo-EM to study the mechanical properties and the gating mechanism of NOMPC. (b) The physiological function of MS channels. We are particularly keen about pursuing our recent discovery that dOSCA is an intrinsic mechano-sensor of the lysosome and dOSCA mutant flies exhibit impaired lysosome-mediated degradation, synaptic loss and progressive motor deficits. (3) Uncovering mechanisms underlying dendrite and axon regeneration after injury. Why do different types of neurons differ in their ability to regenerate their axon or dendrite after injury? What factors can enhance or inhibit regeneration? We find da neurons to be an excellent system to study these problems. Recently, we discovered novel roles of MS channels (Piezo and dOSCA) in axon regeneration and neurodegeneration – exciting findings bringing a confluence of our interests in neuron degeneration/regeneration and MS channels.
