title: The role of Sema3-Npn-1 signaling during diaphragm innervation and muscle development.
abstract: Correct innervation of the main respiratory muscle in mammals, namely the thoracic diaphragm, is a crucial pre-requisite for the functionality of this muscle and the viability of the entire organism. Systemic impairment of Sema3A-Npn-1 (Npn-1 is also known as NRP1) signaling causes excessive branching of phrenic nerves in the diaphragm and into the central tendon region, where the majority of misguided axons innervate ectopic musculature. To elucidate whether these ectopic muscles are a result of misguidance of myoblast precursors due to the loss of Sema3A-Npn-1 signaling, we conditionally ablated Npn-1 in somatic motor neurons, which led to a similar phenotype of phrenic nerve defasciculation and, intriguingly, also formation of innervated ectopic muscles. We therefore hypothesize that ectopic myocyte fusion is caused by additional factors released by misprojecting growth cones. Slit2 and its Robo receptors are expressed by phrenic motor axons and migrating myoblasts, respectively, during innervation of the diaphragm. In vitro analyses revealed a chemoattractant effect of Slit2 on primary diaphragm myoblasts. Thus, we postulate that factors released by motor neuron growth cones have an influence on the migration properties of myoblasts during establishment of the diaphragm.
authors.affiliation: Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Nußbaumstraße 20, Munich 80336, Germany Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, Neuherberg 85764, Germany maximilian.saller@med.uni-muenchen.de.
authors.forename: Maximilian Michael
authors.identifier: 0000-0001-8774-7892
authors.initials: MM
authors.lastname: Saller
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, Neuherberg 85764, Germany Institute of Physiology, Department of Physiological Genomics, Ludwig-Maximilians-University (LMU), Schillerstraße 46, Munich 80336, Germany.
authors.forename: Rosa-Eva
authors.initials: RE
authors.lastname: Huettl
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, Neuherberg 85764, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Hanuschick
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, Neuherberg 85764, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Amend
authors.affiliation: Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Nußbaumstraße 20, Munich 80336, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Alberton
authors.affiliation: Experimental Surgery and Regenerative Medicine, Department of Surgery, Ludwig-Maximilians-University (LMU), Nußbaumstraße 20, Munich 80336, Germany.
authors.forename: Attila
authors.initials: A
authors.lastname: Aszodi
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstraße 1, Neuherberg 85764, Germany Bernstein Network for Computational Neuroscience, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Huber
mesh_terms: D000818:Animals; D000071448:Axon Fasciculation; D003964:Diaphragm / Q000196:embryology / Q000294:innervation* / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D024510:Muscle Development; D032446:Myoblasts / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D039942:Neuropilin-1 / Q000378:metabolism*; D010791:Phrenic Nerve / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D040121:Semaphorin-3A / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D013710:Tendons / Q000378:metabolism; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D039942:Neuropilin-1; D011971:Receptors, Immunologic; D040121:Semaphorin-3A; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C488217:Sema3a protein, mouse; C120010:Slit1 protein, mouse
keywords: Axon pathfinding; Diaphragm; Muscle development; Npn-1; Phrenic nerve; Sema3a