title: Loss of Drosophila melanogaster p21-activated kinase 3 suppresses defects in synapse structure and function caused by spastin mutations.
abstract: Microtubules are dynamic structures that must elongate, disassemble, and be cleaved into smaller pieces for proper neuronal development and function. The AAA ATPase Spastin severs microtubules along their lengths and is thought to regulate the balance between long, stable filaments and shorter fragments that seed extension or are transported. In both Drosophila and humans, loss of Spastin function results in reduction of synaptic connections and disabling motor defects. To gain insight into how spastin is regulated, we screened the Drosophila melanogaster genome for deletions that modify a spastin overexpression phenotype, eye size reduction. One suppressor region deleted p21-activated kinase 3 (pak3), which encodes a member of the Pak family of actin-regulatory enzymes, but whose in vivo function is unknown. We show that pak3 mutants have only mild synaptic defects at the larval neuromuscular junction, but exhibit a potent genetic interaction with spastin mutations. Aberrant bouton morphology, microtubule distribution, and synaptic transmission caused by spastin loss of function are all restored to wild type when pak3 is simultaneously reduced. Neuronal overexpression of pak3 induces actin-rich thin projections, suggesting that it functions in vivo to promote filopodia during presynaptic terminal arborization. pak3 therefore regulates synapse development in vivo, and when mutated, suppresses the synaptic defects that result from spastin loss.
authors.affiliation: Department of Biology/Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Emily F
authors.initials: EF
authors.lastname: Ozdowski
authors.forename: Sophia
authors.initials: S
authors.lastname: Gayle
authors.forename: Hong
authors.initials: H
authors.lastname: Bao
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Nina T
authors.initials: NT
authors.lastname: Sherwood
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000483:Alleles; D000818:Animals; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure; D004843:Epistasis, Genetic; D005123:Eye / Q000378:metabolism; D015870:Gene Expression; D055106:Genome-Wide Association Study; D058977:Molecular Sequence Annotation; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure*; D054462:p21-Activated Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; C099277:Pak protein, Drosophila; D054462:p21-Activated Kinases; D000251:Adenosine Triphosphatases; C501874:spas protein, Drosophila