Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth

Parthiv Haldipur, Gwendolyn S. Gillies, Olivia K. Janson, Victor V. Chizhikov, Divakar S. Mithal, Richard J Miller, Kathleen J. Millen

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish (US)
Article numbere03962
JournaleLife
Volume3
DOIs
StatePublished - 2014

Keywords

  • Cxcl12
  • cerebellum
  • developmental biology
  • foxc1
  • mouse
  • neurodevelopmental disorder
  • neuroscience
  • radial glia
  • stem cells

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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