title: Transcallosal Projections Require Glycoprotein M6-Dependent Neurite Growth and Guidance.
abstract: The function of mature neurons critically relies on the developmental outgrowth and projection of their cellular processes. It has long been postulated that the neuronal glycoproteins M6a and M6b are involved in axon growth because these four-transmembrane domain-proteins of the proteolipid protein family are highly enriched on growth cones, but in vivo evidence has been lacking. Here, we report that the function of M6 proteins is required for normal axonal extension and guidance in vivo. In mice lacking both M6a and M6b, a severe hypoplasia of axon tracts was manifested. Most strikingly, the corpus callosum was reduced in thickness despite normal densities of cortical projection neurons. In single neuron tracing, many axons appeared shorter and disorganized in the double-mutant cortex, and some of them were even misdirected laterally toward the subcortex. Probst bundles were not observed. Upon culturing, double-mutant cortical and cerebellar neurons displayed impaired neurite outgrowth, indicating a cell-intrinsic function of M6 proteins. A rescue experiment showed that the intracellular loop of M6a is essential for the support of neurite extension. We propose that M6 proteins are required for proper extension and guidance of callosal axons that follow one of the most complex trajectories in the mammalian nervous system.
authors.affiliation: Division of Brain Function, National Institute of Genetics, Graduate University for Advanced Studies (Sokendai), Mishima 411-8540, Japan.
authors.forename: Sakura
authors.initials: S
authors.lastname: Mita
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D-37075 Goettingen, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: de Monasterio-Schrader
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D-37075 Goettingen, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Fünfschilling
authors.affiliation: Division of Brain Function, National Institute of Genetics, Graduate University for Advanced Studies (Sokendai), Mishima 411-8540, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Kawasaki
authors.affiliation: Division of Neurogenetics, National Institute of Genetics, Graduate University for Advanced Studies (Sokendai), Mishima 411-8540, Japan.
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Mizuno
authors.affiliation: Division of Neurogenetics, National Institute of Genetics, Graduate University for Advanced Studies (Sokendai), Mishima 411-8540, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Iwasato
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D-37075 Goettingen, Germany.
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D-37075 Goettingen, Germany.
authors.forename: Hauke B
authors.initials: HB
authors.lastname: Werner
authors.affiliation: Division of Brain Function, National Institute of Genetics, Graduate University for Advanced Studies (Sokendai), Mishima 411-8540, Japan.
authors.forename: Tatsumi
authors.initials: T
authors.lastname: Hirata
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000502:physiology; D003337:Corpus Callosum / Q000166:cytology* / Q000502:physiology*; D004622:Embryo, Mammalian; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018991:Myelin Proteolipid Protein / Q000172:deficiency / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D009687:Nuclear Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C511143:Bcl11b protein, mouse; C000624101:Cux1 protein, mouse; C083480:Gpm6a protein, mouse; C083481:Gpm6b protein, mouse; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C047516:Plp1 protein, mouse; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins
keywords: Gpm6a; Gpm6b; Plp1; axon pathfinding; corpus callosum