title: Integration of a retrograde signal during synapse formation by glia-secreted TGF-β ligand.
abstract: Glial cells are crucial regulators of synapse formation, elimination, and plasticity [1, 2]. In vitro studies have begun to identify glial-derived synaptogenic factors [1], but neuron-glia signaling events during synapse formation in vivo remain poorly defined. The coordinated development of pre- and postsynaptic compartments at the Drosophila neuromuscular junction (NMJ) depends on a muscle-secreted retrograde signal, the TGF-β/BMP Glass bottom boat (Gbb) [3, 4]. Muscle-derived Gbb activates the TGF-β receptors Wishful thinking (Wit) and either Saxophone (Sax) or Thick veins (Tkv) in motor neurons [3, 4]. This induces phosphorylation of Mad (P-Mad) in motor neurons, its translocation into the nucleus with a co-Smad, and activation of transcriptional programs controlling presynaptic bouton growth [5]. Here we show that NMJ glia release the TGF-β ligand Maverick (Mav), which likely activates the muscle activin-type receptor Punt to potently modulate Gbb-dependent retrograde signaling and synaptic growth. Loss of glial Mav results in strikingly reduced P-Mad at NMJs, decreased Gbb transcription in muscle, and in turn reduced muscle-to-motor neuron retrograde TGF-β/BMP signaling. We propose that by controlling Gbb release from muscle, glial cells fine tune the ability of motor neurons to extend new synaptic boutons in correlation to muscle growth. Our work identifies a novel glia-derived synaptogenic factor by which glia modulate synapse formation in vivo.
authors.affiliation: Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605-2324, USA.
authors.forename: Yuly
authors.initials: Y
authors.lastname: Fuentes-Medel
authors.forename: James
authors.initials: J
authors.lastname: Ashley
authors.forename: Romina
authors.initials: R
authors.lastname: Barria
authors.forename: Rachel
authors.initials: R
authors.lastname: Maloney
authors.forename: Marc
authors.initials: M
authors.lastname: Freeman
authors.forename: Vivian
authors.initials: V
authors.lastname: Budnik
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D009046:Motor Neurons / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000254:growth & development* / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C108633:Dad protein, Drosophila; D029721:Drosophila Proteins; C112506:MAD protein, Drosophila; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C089440:gbb protein, Drosophila; C415352:mav protein, Drosophila