Presynaptic LRP4 Directs Synapse Development and Cytoskeletal Organization at the Drosophila Neuromuscular Junction
Abstract
Synapse development requires multiple signaling pathways to accomplish the myriad of steps needed to ensure a successful connection. Transmembrane receptors on the cell surface are optimally positioned to facilitate communication between the synapse and the rest of the neuron and often function as synaptic organizers to synchronize downstream signaling events. One such organizer, the LDL receptor-related protein LRP4, is a cell surface receptor most well-studied postsynaptically at mammalian neuromuscular junctions. Recent work, however, has identified emerging roles for LRP4 as a presynaptic molecule, but how LRP4 acts as a presynaptic organizer, what roles LRP4 plays in organizing presynaptic biology, and the downstream mechanisms of LRP4 remain incompletely understood. Here we show that LRP4 functions presynaptically at Drosophila neuromuscular synapses, acting in motor neurons to instruct multiple aspects of pre- and postsynaptic development. Loss of presynaptic LRP4 results in a range of developmental defects, impairing active zone organization, synapse growth, physiological function, microtubule organization, synaptic ultrastructure, and synapse maturation. We further demonstrate that LRP4 promotes most aspects of presynaptic development via a downstream SR-protein kinase, SRPK79D. In the absence of lrp4, SRPK79D overexpression suppresses the lrp4-associated synaptic defects. These data demonstrate a function for LRP4 as a peripheral synaptic organizer acting presynaptically, highlight a downstream mechanism conserved with CNS function, and indicate previously unappreciated roles for LRP4 in cytoskeletal organization, synapse maturation, and active zone organization, underscoring its developmental importance.
Subject Area
Neurosciences|Developmental biology|Genetics
Recommended Citation
DePew, Alison T, "Presynaptic LRP4 Directs Synapse Development and Cytoskeletal Organization at the Drosophila Neuromuscular Junction" (2023). ProQuest ETD Collection - Thomas Jefferson University. AAI30812508.
https://jdc.jefferson.edu/dissertations/AAI30812508
