title: Gli3 controls corpus callosum formation by positioning midline guideposts during telencephalic patterning.
abstract: The corpus callosum (CC) represents the major forebrain commissure connecting the 2 cerebral hemispheres. Midline crossing of callosal axons is controlled by several glial and neuronal guideposts specifically located along the callosal path, but it remains unknown how these cells acquire their position. Here, we show that the Gli3 hypomorphic mouse mutant Polydactyly Nagoya (Pdn) displays agenesis of the CC and mislocation of the glial and neuronal guidepost cells. Using transplantation experiments, we demonstrate that agenesis of the CC is primarily caused by midline defects. These defects originate during telencephalic patterning and involve an up-regulation of Slit2 expression and altered Fgf and Wnt/β-catenin signaling. Mutations in sprouty1/2 which mimic the changes in these signaling pathways cause a disorganization of midline guideposts and CC agenesis. Moreover, a partial recovery of midline abnormalities in Pdn/Pdn;Slit2(-/-) embryos mutants confirms the functional importance of correct Slit2 expression levels for callosal development. Hence, Gli3 controlled restriction of Fgf and Wnt/β-catenin signaling and of Slit2 expression is crucial for positioning midline guideposts and callosal development.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
authors.forename: Dario
authors.initials: D
authors.lastname: Magnani
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hasenpusch-Theil
authors.forename: Carine
authors.initials: C
authors.lastname: Benadiba
authors.forename: Tian
authors.initials: T
authors.lastname: Yu
authors.forename: M Albert
authors.initials: MA
authors.lastname: Basson
authors.forename: David J
authors.initials: DJ
authors.lastname: Price
authors.forename: Cécile
authors.initials: C
authors.lastname: Lebrand
authors.forename: Thomas
authors.initials: T
authors.lastname: Theil
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000254:growth & development; D016000:Cluster Analysis; D003337:Corpus Callosum / Q000196:embryology / Q000254:growth & development*; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000502:physiology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009924:Organ Culture Techniques; D017689:Polydactyly / Q000235:genetics; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology; D013687:Telencephalon / Q000196:embryology / Q000254:growth & development*; D015854:Up-Regulation / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000502:physiology; D000074290:Zinc Finger Protein Gli3; D051176:beta Catenin / Q000502:physiology; D000098552:Slit Homolog 2 Protein
chemical_list: C465571:Gli3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D017468:Receptors, Fibroblast Growth Factor; D000074290:Zinc Finger Protein Gli3; D051176:beta Catenin; D000098552:Slit Homolog 2 Protein