title: Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth.
abstract: Loss of Foxc1 is associated with Dandy-Walker malformation, the most common human cerebellar malformation characterized by cerebellar hypoplasia and an enlarged posterior fossa and fourth ventricle. Although expressed in the mouse posterior fossa mesenchyme, loss of Foxc1 non-autonomously induces a rapid and devastating decrease in embryonic cerebellar ventricular zone radial glial proliferation and concurrent increase in cerebellar neuronal differentiation. Subsequent migration of cerebellar neurons is disrupted, associated with disordered radial glial morphology. In vitro, SDF1α, a direct Foxc1 target also expressed in the head mesenchyme, acts as a cerebellar radial glial mitogen and a chemoattractant for nascent Purkinje cells. Its receptor, Cxcr4, is expressed in cerebellar radial glial cells and conditional Cxcr4 ablation with Nes-Cre mimics the Foxc1-/- cerebellar phenotype. SDF1α also rescues the Foxc1-/- phenotype. Our data emphasizes that the head mesenchyme exerts a considerable influence on early embryonic brain development and its disruption contributes to neurodevelopmental disorders in humans.
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Parthiv
authors.initials: P
authors.lastname: Haldipur
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Gwendolyn S
authors.initials: GS
authors.lastname: Gillies
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Olivia K
authors.initials: OK
authors.lastname: Janson
authors.affiliation: Department of Anatomy and Neurobiology, University of Tennessee Health Sciences Center, Memphis, United States.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Chizhikov
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, United States.
authors.forename: Divakar S
authors.initials: DS
authors.lastname: Mithal
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, United States.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Miller
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Millen
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000235:genetics; D002531:Cerebellum / Q000166:cytology / Q000196:embryology*; D054377:Chemokine CXCL12 / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; D019718:Receptors, CXCR4
keywords: Cxcl12; cerebellum; developmental biology; foxc1; mouse; neurodevelopmental disorder; neuroscience; radial glia; stem cells