title: Loss of Npn1 from motor neurons causes postnatal deficits independent from Sema3A signaling.
abstract: The correct wiring of neuronal circuits is of crucial importance for the function of the vertebrate nervous system. Guidance cues like the neuropilin receptors (Npn) and their ligands, the semaphorins (Sema) provide a tight spatiotemporal control of sensory and motor axon growth and guidance. Among this family of guidance partners the Sema3A-Npn1 interaction has been shown to be of great importance, since defective signaling leads to wiring deficits and defasciculation. For the embryonic stage these defects have been well described, however, also after birth the organism can adapt to new challenges by compensational mechanisms. Therefore, we used the mouse lines Olig2-Cre;Npn1(cond) and Npn1(Sema-) to investigate how postnatal organisms cope with the loss of Npn1 selectively from motor neurons or a systemic dysfunctional Sema3A-Npn1 signaling in the entire organism, respectively. While in Olig2-Cre(+);Npn1(cond-/-) mice clear anatomical deficits in paw posturing, bone structure, as well as muscle and nerve composition became evident, Npn1(Sema-) mutants appeared anatomically normal. Furthermore, Olig2-Cre(+);Npn1(cond) mutants revealed a dysfunctional extensor muscle innervation after single-train stimulation of the N.radial. Interestingly, these mice did not show obvious deficits in voluntary locomotion, however, skilled motor function was affected. In contrast, Npn1(Sema-) mutants were less affected in all behavioral tests and able to improve their performance over time. Our data suggest that loss of Sema3A-Npn1 signaling is not the only cause for the observed deficits in Olig2-Cre(+);Npn1(cond-/-) mice and that additional, yet unknown binding partners for Npn1 may be involved that allow Npn1(Sema-) mutants to compensate for their developmental deficits.
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany. Electronic address: michaela.helmbrecht@helmholtz-muenchen.de.
authors.forename: Michaela S
authors.initials: MS
authors.lastname: Helmbrecht
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Soellner
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Anna M L
authors.initials: AML
authors.lastname: Truckenbrodt
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Sundermeier
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany; DFG-Research Center for Regenerative Therapies Dresden, Technische Universität and Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Cohrs
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany; Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, 85354 Freising-Weihenstephan, Germany; German Center for Diabetes Research (DZD), Ingostädter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.affiliation: Research Unit Analytical Pathology, Insititute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Feuchtinger
authors.affiliation: Research Unit Analytical Pathology, Insititute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: Faculty of Rehabilitation Medicine and Centre for Neuroscience, University of Alberta, Canada.
authors.forename: Karim
authors.initials: K
authors.lastname: Fouad
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany. Electronic address: andrea.huber@helmholtz-muenchen.de.
authors.forename: Andrea B
authors.initials: AB
authors.lastname: Huber
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D001846:Bone Development / Q000235:genetics / Q000502:physiology; D001842:Bone and Bones / Q000196:embryology / Q000294:innervation / Q000378:metabolism; D005552:Forelimb / Q000196:embryology / Q000254:growth & development / Q000294:innervation; D007150:Immunohistochemistry; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000196:embryology / Q000254:growth & development / Q000294:innervation; D009412:Nerve Fibers / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism*; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
chemical_list: C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D039942:Neuropilin-1
keywords: Motor neuron; Npn1; Postnatal development; Sema3A