The nervous system comprises an immense number of diverse cell types organized into defined neural circuits. Defects in neural wiring are associated with numerous neurological disorders, thus investigating the basis for normal circuit formation is critical for understanding how these disorders arise. To form properly wired circuits, neurons must be able to discriminate between correct and incorrect potential partners. To achieve this, neurons express membrane-bound cell adhesion molecules, which serve as molecular signatures and promote recognition between partners. However, given the tremendous number of possible synaptic partners, mechanisms must be in place to diversify the repertoire of molecules available to a neuron. Furthermore, given that dendrites and axons navigate an incredibly dense neural environment, mechanisms must be used both to promote synaptic connections between partners and to prevent connections between inappropriate partners. My studies of Down syndrome cell adhesion molecule 2 (Dscam2) in Drosophila somatosensory circuitry have potential to shed light on these challenges to synaptic specificity. Dscam2 encodes two alternatively spliced isoforms, Dscam2A and Dscam2B, and my results suggest that isoform diversity is critical for somatosensory circuit development. Dscam2 isoforms have been previously shown to bind homophilically to mediate repulsion between neural processes. Thus, Dscam2 isoforms could prevent or permit synaptic connections, based on cell type specific alternative splicing. I propose to determine the role of Dscam2 in patterning somatosensory axons, and central synaptic target dendrites, and to determine the role of isoform diversity in somatosensory circuit assembly and somatosensory-evoked behaviors.
Proper wiring of neural circuits is essential for nervous system function. This proposal seeks to understand the basis for neural patterning and circuit formation during development. Defects in neural wiring are associated with numerous neurological disorders, thus identifying the genes that regulate neural circuit assembly is critical for understanding how pathological disorders arise.
