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Free keywords:
active zone assembly; Drosophila; Liprin-alpha; PP2A; presynaptic differentiation; Syd-1
Abstract:
During synaptic development, presynaptic differentiation occurs as an intrinsic property of axons to form specialized areas of plasma membrane [active zones (AZs)] that regulate exocytosis and endocytosis of synaptic vesicles. Genetic and biochemical studies in vertebrate and invertebrate model systems have identified a number of proteins involved in AZ assembly. However, elucidating the molecular events of AZ assembly in a spatiotemporal manner remains a challenge. Syd-1 (synapse defective-1) and Liprin-alpha have been identified as two master organizers of AZ assembly. Genetic and imaging analyses in invertebrates show that Syd-1 works upstream of Liprin-alpha in synaptic assembly through undefined mechanisms. To understand molecular pathways downstream of Liprin-alpha, we performed a proteomic screen of Liprin-alpha -interacting proteins in Drosophila brains. We identify Drosophila protein phosphatase 2A (PP2A) regulatory subunit B' [Wrd (Well Rounded)] as a Liprin-alpha -interacting protein, and we demonstrate that it mediates the interaction of Liprin-alpha with PP2A holoenzyme and the Liprin-alpha -dependent synaptic localization of PP2A. Interestingly, loss of function in syd-1, liprin-alpha, or wrd shares a common defect in which a portion of synaptic vesicles, dense-core vesicles, and presynaptic cytomatrix proteins ectopically accumulate at the distal, but not proximal, region of motoneuron axons. Strong genetic data show that a linear syd-1/liprin-alpha/wrd pathway in the motoneuron antagonizes glycogen synthase kinase-3 alpha kinase activity to prevent the ectopic accumulation of synaptic materials. Furthermore, we provide data suggesting that the syd-1/liprin-alpha/wrd pathway stabilizes AZ specification at the nerve terminal and that such a novel function is independent of the roles of syd-1/liprin-alpha in regulating the morphology of the T-bar structural protein BRP (Bruchpilot).
