Genetic dissection of the function of hindbrain axonal commissures
| Autor: | Marc Tessier-Lavigne, Alain Chédotal, Chris I. De Zeeuw, Nicolas Renier, Paul Avan, Martijn Schonewille, Aleksandra Badura, Fabrice Giraudet |
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| Přispěvatelé: | Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Neuroscience, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Genentech, Inc. [San Francisco], his project is supported by grants from the 'fondation pour le recherche médicale' (programme Equipe FRM), the Association Française contre les Myopathies (AFM, ASS-SUB06-00123), and the Agence Nationale de la Recherche (ANR-08-MNPS-030-01) to AC. The group of CIDZ was supported by the Dutch Organization for Medical Sciences (ZON-MW), Life Sciences (NWO-ALW), Senter (Neuro-Bsik), Prinses Beatrix Fonds, and the European Community (EEC)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA), Autard, Delphine, Netherlands Institute for Neuroscience (NIN), Neurosciences |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Eye Movements
MESH: Rotarod Performance Test MESH: Mice Knockout Mice Ocular Motility Disorders 0302 clinical medicine MESH: Eye Movements MESH: Behavior Animal Developmental Biology/Developmental Molecular Mechanisms MESH: Animals MESH: Nerve Tissue Proteins Biology (General) Mice Knockout 0303 health sciences Movement Disorders Neuroscience/Behavioral Neuroscience Behavior Animal General Neuroscience Horizontal gaze palsy MESH: Rhombencephalon Climbing fiber Anatomy Commissure Neuroscience/Neurodevelopment MESH: Motor Activity Ophthalmology/Inherited Eye Disorders MESH: Evoked Potentials Auditory medicine.anatomical_structure [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs Evoked Potentials Auditory MESH: Membrane Proteins General Agricultural and Biological Sciences Research Article MESH: Body Patterning MESH: Axons Genetics and Genomics/Animal Genetics QH301-705.5 Recombinant Fusion Proteins Central nervous system Rhombomere Nerve Tissue Proteins Receptors Cell Surface Hindbrain Motor Activity Biology Neurological Disorders General Biochemistry Genetics and Molecular Biology 03 medical and health sciences MESH: Mice Inbred C57BL medicine MESH: Recombinant Fusion Proteins Animals Humans MESH: Ocular Motility Disorders [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs MESH: Mice Body Patterning 030304 developmental biology MESH: Humans General Immunology and Microbiology MESH: Embryo Mammalian Membrane Proteins Embryo Mammalian medicine.disease Axons Mice Inbred C57BL Rhombencephalon Developmental Biology/Neurodevelopment nervous system Rotarod Performance Test Forebrain Axon guidance 030217 neurology & neurosurgery MESH: Movement Disorders |
| Zdroj: | PLoS Biology, Vol 8, Iss 3, p e1000325 (2010) PLoS Biology PLoS Biology, 2010, 8 (3), pp.e1000325. ⟨10.1371/journal.pbio.1000325⟩ PLoS Biology, Public Library of Science, 2010, 8 (3), pp.e1000325. ⟨10.1371/journal.pbio.1000325⟩ PLoS Biology, 8. Public Library of Science PLoS Biology (print), 8(3). Public Library of Science |
| ISSN: | 1545-7885 1544-9173 |
| Popis: | The Robo3 receptor controls midline crossing by axons. Deleting Robo3 in specific commissural neurons with a conditional knockout reveals their contribution to sensory and motor integration, and models human neurological conditions. In Bilateria, many axons cross the midline of the central nervous system, forming well-defined commissures. Whereas in mammals the functions of commissures in the forebrain and in the visual system are well established, functions at other axial levels are less clearly understood. Here, we have dissected the function of several hindbrain commissures using genetic methods. By taking advantage of multiple Cre transgenic lines, we have induced site-specific deletions of the Robo3 receptor. These lines developed with the disruption of specific commissures in the sensory, motor, and sensorimotor systems, resulting in severe and permanent functional deficits. We show that mice with severely reduced commissures in rhombomeres 5 and 3 have abnormal lateral eye movements and auditory brainstem responses, respectively, whereas mice with a primarily uncrossed climbing fiber/Purkinje cell projection are strongly ataxic. Surprisingly, although rerouted axons remain ipsilateral, they still project to their appropriate neuronal targets. Moreover, some Cre;Robo3 lines represent potential models that can be used to study human syndromes, including horizontal gaze palsy with progressive scoliosis (HGPPS). To our knowledge, this study is one of the first to link defects in commissural axon guidance with specific cellular and behavioral phenotypes. Author Summary Coordination of the left and right sides of the body requires the action of neurons whose axons cross the nervous system midline. The precise contributions of “commissural” neurons to sensory and motor functions remain poorly understood. To probe these crossing circuits, we took advantage of the recent finding that the Robo3 axon guidance receptor is required for midline crossing by axons at most axial levels. A Robo3 conditional knockout mouse line was generated, allowing Robo3 to be deleted in selective neuronal populations. This led to disruption of specific commissures in the sensory, motor, and sensorimotor systems, and resulted in severe but specific functional deficits. Surprisingly, although rerouted axons do not cross the midline, they still project to their appropriate neuronal targets, suggesting that midline crossing is not required to complete the axonal guidance program of those neurons. Moreover, some of the mouse lines represent good models for human syndromes, including horizontal gaze palsy with progressive scoliosis (HGPPS), which is characterized by deficits in coordinated eye movements. This study links defects in commissural axon guidance with specific and dramatic behavioral phenotypes. |
| Databáze: | OpenAIRE |
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