Unrestricted synaptic growth in spinster-a late endosomal protein implicated in TGF-beta-mediated synaptic growth regulation.
In a genetic screen for genes that control synapse development, we have identified spinster (spin), which encodes a multipass transmembrane protein. spin mutant synapses reveal a 200% increase in bouton number and a deficit in presynaptic release. We demonstrate that spin is expressed in both nerve and muscle and is required both pre- and postsynaptically for normal synaptic growth. We have localized Spin to a late endosomal compartment and present evidence for altered endosomal/lysosomal function in spin. We also present evidence that synaptic overgrowth in spin is caused by enhanced/misregulated TGF-beta signaling. TGF-beta receptor mutants show dose-dependent suppression of synaptic overgrowth in spin. Furthermore, mutations in Dad, an inhibitory Smad, cause synapse overgrowth. We present a model for synaptic growth control with implications for the etiology of lysosomal storage and neurodegenerative disease.
Sweeney
Sean T
ST
Department of Biochemistry, 513 Parnassus Avenue, HSE 901, University of California, San Francisco, San Francisco, CA 94143, USA.
Davis
Graeme W
GW
D000818:Animals; D002451:Cell Compartmentation / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D029721:Drosophila Proteins / Q000172:deficiency* / Q000235:genetics; D004331:Drosophila melanogaster / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000002:abnormalities / Q000254:growth & development / Q000294:innervation; D009154:Mutation / Q000235:genetics; D009420:Nervous System / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D009469:Neuromuscular Junction / Q000002:abnormalities / Q000254:growth & development / Q000473:pathology; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta; C429164:spin protein, Drosophila