Elucidating the cellular and molecular mechanisms underlying class-specific dendritogenesis is important morphologically, as proper dendrite development is essential for the establishment and maintenance of functional neural circuitry, as well as in relation to neurological and neurodegenerative disease in which dendritic abnormalities may manifest as impaired cognitive function. Drosophila melanogaster has emerged as a powerful model for dissecting these mechanisms. While significant evidence demonstrates that complex transcriptional regulatory programs function to generate cell-type specific dendritic morphologies, what remains poorly understood is the downstream implementation of these programs and what cellular, molecular and biological processes are recruited to enable these changes in dendrite morphology. The current proposal will address this knowledge gap by focusing on key downstream effectors by which the evolutionarily conserved Cut homeodomain transcription factor mediates class-specific dendrite arborization and homeostasis. We will test three central hypotheses: 1) that Cut differentially regulates class specific sensory neuron dendrite arborization and homeostasis via regulation of the basal autophagy pathway;2) that a novel zinc-finger BED- type protein encoded by CG3995 functions as a downstream efector of Cut and functionally interacts with ribosomal proteins to direct cell-type specific dendrite morphogenesis;and 3) that the evolutionarily conserved Hox proteins, Antennapedia and Sex Combs Reduced, function with Cut to differentially mediate cell-type specific dendritic morphologies. The short-term impact of the proposed studies will be novel insight into the cellular and molecular machinery by which transcriptional control exerts effects on differential dendrite morphogenesis in Drosophila. Ultimately, these studies have the potential to identify evolutionarily conserved regulatory mechanisms that govern dendrite development/homeostasis in humans and potentially contribute to our understanding of how derangements in these cellular processes may underlie neurological and neurodegenerative disease states.
Dendrite are primarily specialized to receive and process neuronal inputs and thus the molecular mechanisms that drive dendritic morphology are critical to establishing and maintaining a functional nervous system. This functional role is illustrated in a diverse array of neuropathological and neurodegenerative disease states including Alzheimer's, mental retardation, and Autism in which strong neuroanatomical correlates exist between dendrite defects and cognitive impairments. The proposed studies aim to elucidate key molecular and cellular programs that function in directing and maintaining cell-type specific dendrite morphogenesis and homeostasis.
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