title: The Drosophila LEM-domain protein MAN1 antagonizes BMP signaling at the neuromuscular junction and the wing crossveins.
abstract: BMP signaling responses are refined by distinct secreted and intracellular antagonists in different cellular and temporal contexts. Here, we show that the nuclear LEM-domain protein MAN1 is a tissue-specific antagonist of BMP signaling in Drosophila. MAN1 contains two potential Mad-binding sites. We generated MAN1DeltaC mutants, harbouring a MAN1 protein that lacks part of the C-terminus including the RNA recognition motif, a putative Mad-binding domain. MAN1DeltaC mutants show wing crossvein (CV) patterning defects but no detectable alterations in nuclear morphology. MAN1(DeltaC) pupal wings display expanded phospho-Mad (pMad) accumulation and ectopic expression of the BMP-responsive gene crossveinless-2 (cv-2) indicating that MAN1 restricts BMP signaling. Conversely, MAN1 overexpression in wing imaginal discs inhibited crossvein development and BMP signaling responses. MAN1 is expressed at high levels in pupal wing veins and can be activated in intervein regions by ectopic BMP signaling. The specific upregulation of MAN1 in pupal wing veins may thus represent a negative feedback circuit that limits BMP signaling during CV formation. MAN1DeltaC flies also show reduced locomotor activity, and electrophysiology recordings in MAN1DeltaC larvae uncover a new presynaptic role of MAN1 at the neuromuscular junction (NMJ). Genetic interaction experiments suggest that MAN1 is a BMP signaling antagonist both at the NMJ and during CV formation.
authors.affiliation: Department of Developmental Biology, Wenner-Gren Institute, Stockholm University, S-10691 Stockholm, Sweden. nicole.wagner@uni-wuerzburg.de
authors.forename: Nicole
authors.initials: N
authors.lastname: Wagner
authors.forename: Annika
authors.initials: A
authors.lastname: Weyhersmüller
authors.forename: Anna
authors.initials: A
authors.lastname: Blauth
authors.forename: Tamara
authors.initials: T
authors.lastname: Schuhmann
authors.forename: Manfred
authors.initials: M
authors.lastname: Heckmann
authors.forename: Georg
authors.initials: G
authors.lastname: Krohne
authors.forename: Christos
authors.initials: C
authors.lastname: Samakovlis
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D017931:DNA Primers; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000378:metabolism / Q000502:physiology*; D004591:Electrophoresis, Polyacrylamide Gel; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D009469:Neuromuscular Junction / Q000196:embryology*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014921:Wings, Animal / Q000196:embryology*
chemical_list: D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D029721:Drosophila Proteins; C509056:MAN1 protein, Drosophila; D009687:Nuclear Proteins