ISDN2014_0119: Mesenchymal Foxc1 non‐autonomously controls cerebellar development through SDF1α‐CXCR4 maintenance of radial glial cells

Foxc1 mutations have been implicated in Dandy–Walker malformation (DWM), the most common human cerebellar malformation diagnosed by an enlarged posterior fossa and fourth ventricle, and cerebellar hypoplasia. Although loss of this transcription factor causes developmental cerebellar pathology, it is not expressed in the developing cerebellum. Rather it is widely expressed in embryonic mesoderm and mesenchyme including the developing posterior fossa beginning ∼e12.5 in mice. We now demonstrate that loss of mesenchymal Foxc1 expression at e12.5 induces a rapid and devastating reduction in cerebellar ventricular zone radial glial proliferation and survival, and a concurrent dramatic increase in cerebellar neuronal differentiation as early as e13.5. Subsequent radial migration of remaining Purkinje cells is also disrupted, associated with a disordered radial glial morphology. Through a combination of in vitro proliferation and migration assays, we determine that SDF1 , a direct downstream target of Foxc1, expressed in the head mesenchyme, acts as a cerebellar radial glial survival factor and mitogen, and also a chemoattractant for nascent Purkinje cells. We show that the SDF1 receptor, Cxcr4, is specifically expressed in cerebellar radial glial cells. Ablation of Cxcr4 in cerebellar radial glial cells largely mimics the Foxc1 mutant cerebellar phenotype. Our data demonstrates that SDF1 -Cxcr4 signaling is essential for radial glial survival and function. This is an earlier and more fundamental role for this important signaling pathway in cerebellar development than previously reported. Our DWM and Foxc1 data contributes to a growing body of evidence supporting a paradigm shift. The brain does not develop in isolation. Rather, the head mesenchyme exerts considerable influence on early embryonic brain development.