title: Sumoylated MEF2A coordinately eliminates orphan presynaptic sites and promotes maturation of presynaptic boutons.
abstract: Presynaptic differentiation of axons plays a fundamental role in the establishment of neuronal connectivity. However, the mechanisms that govern presynaptic differentiation in the brain remain largely to be elucidated. We report that knockdown of the transcription factor MEF2A in primary neurons and importantly in the rat cerebellar cortex in vivo robustly increases the density of orphan presynaptic sites. Remarkably, the sumoylated transcriptional repressor form of MEF2A drives the suppression of orphan presynaptic sites. We also identify the gene encoding synaptotagmin 1 (Syt1), which acts locally at presynaptic sites, as a direct repressed target gene of sumoylated MEF2A in neurons, and demonstrate that repression of Syt1 mediates MEF2A-dependent elimination of orphan presynaptic sites. Finally, we uncover a role for the MEF2A-induced elimination of orphan presynaptic sites in the accumulation of presynaptic material at large maturing presynaptic boutons. Collectively, these findings define sumoylated MEF2A and Syt1 as components of a novel cell-intrinsic mechanism that orchestrates presynaptic differentiation in the mammalian brain. Our study has important implications for understanding neuronal connectivity in brain development and disease.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamada
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.forename: Ju
authors.initials: J
authors.lastname: Huang
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: Azad
authors.initials: A
authors.lastname: Bonni
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002531:Cerebellum / Q000166:cytology; D047369:Chromatin Immunoprecipitation; D000076122:Disks Large Homolog 4 Protein; D024202:Electrophoretic Mobility Shift Assay; D018274:Electroporation; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D017729:Presynaptic Terminals / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D020318:Rats, Long-Evans; D058207:Sumoylation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013997:Time Factors; D014162:Transfection; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism
chemical_list: C113688:Bsn protein, rat; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578037:MEF2A protein, rat; D008565:Membrane Proteins; D018006:Myogenic Regulatory Factors; D009419:Nerve Tissue Proteins; C494706:Vamp2 protein, rat; D050988:Vesicle-Associated Membrane Protein 2; D049452:Green Fluorescent Proteins