Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth.
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.
['Haldipur|Parthiv|P|', 'Gillies|Gwendolyn S|GS|', 'Janson|Olivia K|OK|', 'Chizhikov|Victor V|VV|', 'Mithal|Divakar S|DS|', 'Miller|Richard J|RJ|', 'Millen|Kathleen J|KJ|']
D000818:Animals D002454:Cell Differentiation D049109:Cell Proliferation D002531:Cerebellum D054377:Chemokine CXCL12 D051858:Forkhead Transcription Factors D008648:Mesoderm D051379:Mice D018345:Mice, Knockout D019718:Receptors, CXCR4 D015398:Signal Transduction
foxc1 mouse neurodevelopmental disorder Cxcl12 cerebellum developmental biology neuroscience radial glia stem cells