title: Loss of lysophosphatidic acid receptor LPA1 alters oligodendrocyte differentiation and myelination in the mouse cerebral cortex.
abstract: Lysophosphatidic acid (LPA) is an intercellular signaling lipid that regulates multiple cellular functions, acting through specific G-protein coupled receptors (LPA(1-6)). Our previous studies using viable Malaga variant maLPA1-null mice demonstrated the requirement of the LPA1 receptor for normal proliferation, differentiation, and survival of the neuronal precursors. In the cerebral cortex LPA1 is expressed extensively in differentiating oligodendrocytes, in parallel with myelination. Although exogenous LPA-induced effects have been investigated in myelinating cells, the in vivo contribution of LPA1 to normal myelination remains to be demonstrated. This study identified a relevant in vivo role for LPA1 as a regulator of cortical myelination. Immunochemical analysis in adult maLPA1-null mice demonstrated a reduction in the steady-state levels of the myelin proteins MBP, PLP/DM20, and CNPase in the cerebral cortex. The myelin defects were confirmed using magnetic resonance spectroscopy and electron microscopy. Stereological analysis limited the defects to adult differentiating oligodendrocytes, without variation in the NG2+ precursor cells. Finally, a possible mechanism involving oligodendrocyte survival was demonstrated by the impaired intracellular transport of the PLP/DM20 myelin protein which was accompanied by cellular loss, suggesting stress-induced apoptosis. These findings describe a previously uncharacterized in vivo functional role for LPA1 in the regulation of oligodendrocyte differentiation and myelination in the CNS, underlining the importance of the maLPA1-null mouse as a model for the study of demyelinating diseases.
authors.affiliation: Laboratorio de Investigación, UGC Intercentros de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional de Málaga y Virgen de la Victoria, Hospital Civil, Pabellón 5, Planta Sótano, Plaza del Hospital Civil s/n, 29009, Málaga, Spain.|Department of Neurology, H. Houston Merritt Clinical Research Center, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Beatriz
authors.initials: B
authors.lastname: García-Díaz
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols', Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), 28029, Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Riquelme
authors.affiliation: Instituto de Investigaciones Biomédicas 'Alberto Sols', Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), 28029, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Varela-Nieto
authors.affiliation: Departamento de Biología Celular, Genética y Fisiología, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29071, Málaga, Spain.
authors.forename: Antonio Jesús
authors.initials: AJ
authors.lastname: Jiménez
authors.affiliation: Departamento de Anatomía y Medicina Legal, Universidad de Málaga, 29071, Málaga, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: de Diego
authors.affiliation: ECAI de Microscopía, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional de Málaga y Virgen de la Victoria, 29010, Málaga, Spain.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Gómez-Conde
authors.affiliation: Laboratorio de Investigación, UGC Intercentros de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional de Málaga y Virgen de la Victoria, Hospital Civil, Pabellón 5, Planta Sótano, Plaza del Hospital Civil s/n, 29009, Málaga, Spain.|Division of Cell Biology I, The Netherlands Cancer Institute, 1066CX, Amsterdam, The Netherlands.
authors.forename: Elisa
authors.initials: E
authors.lastname: Matas-Rico
authors.affiliation: Departamento de Fisiología Humana y Educación Físico Deportiva, Universidad de Málaga, 29071, Málaga, Spain.
authors.forename: José Ángel
authors.initials: JÁ
authors.lastname: Aguirre
authors.affiliation: Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Centre, The Scripps Research Institute, La Jolla, CA, 92037, USA.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.affiliation: Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29071, Málaga, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Pedraza
authors.affiliation: Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29071, Málaga, Spain.
authors.forename: Luis Javier
authors.initials: LJ
authors.lastname: Santín
authors.affiliation: Neurology Service, UGC Intercentros de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional de Málaga y Virgen de la Victoria, Universidad de Málaga, 29010, Málaga, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernández
authors.affiliation: Laboratorio de Medicina Regenerativa, UGC de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, 29010, Málaga, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.affiliation: Laboratorio de Investigación, UGC Intercentros de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional de Málaga y Virgen de la Victoria, Hospital Civil, Pabellón 5, Planta Sótano, Plaza del Hospital Civil s/n, 29009, Málaga, Spain. guillermo.estivill@ibima.eu.|ECAI de Microscopía, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional de Málaga y Virgen de la Victoria, 29010, Málaga, Spain. guillermo.estivill@ibima.eu.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Estivill-Torrús
mesh_terms: D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000648:ultrastructure; D002454:Cell Differentiation; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000502:physiology*; D021381:Protein Transport; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000502:physiology*
chemical_list: D009185:Myelin Proteins; D049368:Receptors, Lysophosphatidic Acid
keywords: Cerebral cortex; Lysophosphatidic acid receptor; Myelin; Oligodendrocyte