title: Diverging roles for Lrp4 and Wnt signaling in neuromuscular synapse development during evolution.
abstract: Motor axons approach muscles that are prepatterned in the prospective synaptic region. In mice, prepatterning of acetylcholine receptors requires Lrp4, a LDLR family member, and MuSK, a receptor tyrosine kinase. Lrp4 can bind and stimulate MuSK, strongly suggesting that association between Lrp4 and MuSK, independent of additional ligands, initiates prepatterning in mice. In zebrafish, Wnts, which bind the Frizzled (Fz)-like domain in MuSK, are required for prepatterning, suggesting that Wnts may contribute to prepatterning and neuromuscular development in mammals. We show that prepatterning in mice requires Lrp4 but not the MuSK Fz-like domain. In contrast, prepatterning in zebrafish requires the MuSK Fz-like domain but not Lrp4. Despite these differences, neuromuscular synapse formation in zebrafish and mice share similar mechanisms, requiring Lrp4, MuSK, and neuronal Agrin but not the MuSK Fz-like domain or Wnt production from muscle. Our findings demonstrate that evolutionary divergent mechanisms establish muscle prepatterning in zebrafish and mice.
authors.affiliation: Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University Medical School, New York, New York 10016, USA;
authors.forename: Leonor
authors.identifier: 0000-0002-1509-0024
authors.initials: L
authors.lastname: Remédio
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Gribble
authors.affiliation: Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University Medical School, New York, New York 10016, USA;
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University Medical School, New York, New York 10016, USA;
authors.forename: Natalie
authors.initials: N
authors.lastname: Kim
authors.affiliation: Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University Medical School, New York, New York 10016, USA;
authors.forename: Peter T
authors.initials: PT
authors.lastname: Hallock
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, New York 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA; Department of Neurology, Columbia University, New York, New York 10032, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Delestrée
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, New York 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA; Department of Neurology, Columbia University, New York, New York 10032, USA.
authors.forename: George Z
authors.initials: GZ
authors.lastname: Mentis
authors.affiliation: Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University Medical School, New York, New York 10016, USA;
authors.forename: Robert C
authors.initials: RC
authors.lastname: Froemke
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;
authors.forename: Michael
authors.initials: M
authors.lastname: Granato
authors.affiliation: Molecular Neurobiology Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University Medical School, New York, New York 10016, USA;
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Burden
mesh_terms: D000818:Animals; D005075:Biological Evolution; D019521:Body Patterning / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000196:embryology* / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D000099249:Proteoglycan Link Protein
chemical_list: D016326:Extracellular Matrix Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D020794:Receptor Protein-Tyrosine Kinases; D029961:Zebrafish Proteins; C480570:Hapln4 protein, mouse; D000099249:Proteoglycan Link Protein; C490829:MuSK protein, zebrafish; C511695:MuSK protein, mouse
keywords: Frizzled; Lrp4; MuSK; Wnt; neuromuscular; synapse