title: Retrograde BMP signaling modulates rapid activity-dependent synaptic growth via presynaptic LIM kinase regulation of cofilin.
abstract: The Drosophila neuromuscular junction (NMJ) is capable of rapidly budding new presynaptic varicosities over the course of minutes in response to elevated neuronal activity. Using live imaging of synaptic growth, we characterized this dynamic process and demonstrated that rapid bouton budding requires retrograde bone morphogenic protein (BMP) signaling and local alteration in the presynaptic actin cytoskeleton. BMP acts during development to provide competence for rapid synaptic growth by regulating the levels of the Rho-type guanine nucleotide exchange factor Trio, a transcriptional output of BMP-Smad signaling. In a parallel pathway, we find that the BMP type II receptor Wit signals through the effector protein LIM domain kinase 1 (Limk) to regulate bouton budding. Limk interfaces with structural plasticity by controlling the activity of the actin depolymerizing protein Cofilin. Expression of constitutively active or inactive Cofilin in motor neurons demonstrates that increased Cofilin activity promotes rapid bouton formation in response to elevated synaptic activity. Correspondingly, the overexpression of Limk, which inhibits Cofilin, inhibits bouton budding. Live imaging of the presynaptic F-actin cytoskeleton reveals that activity-dependent bouton addition is accompanied by the formation of new F-actin puncta at sites of synaptic growth. Pharmacological disruption of actin turnover inhibits bouton budding, indicating that local changes in the actin cytoskeleton at pre-existing boutons precede new budding events. We propose that developmental BMP signaling potentiates NMJs for rapid activity-dependent structural plasticity that is achieved by muscle release of retrograde signals that regulate local presynaptic actin cytoskeletal dynamics.
authors.affiliation: The Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Piccioli
authors.forename: J Troy
authors.initials: JT
authors.lastname: Littleton
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D004330:Drosophila; D054461:Lim Kinases / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism; D009469:Neuromuscular Junction / Q000254:growth & development* / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D019485:Bone Morphogenetic Proteins; D054461:Lim Kinases; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: BMP; Drosophila; actin; neuromuscular junction; synapse formation; synaptic plasticity