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.DOI: http://dx.doi.org/10.7554/eLife.03962.001

Yap and Taz play a crucial role in neural crest-derived craniofacial development

“…Fox transcription factors are key regulators of embryogenesis and control fundamental biological processes, including cell proliferation, fate determination, differentiation and growth (Kaufmann and Knochel, 1996;Kume et al, 1998Kume et al, , 2001Kidson et al, 1999;Tuteja and Kaestner, 2007a,b;Benayoun et al, 2011;Haldipur et al, 2014). Notably, Fox genes are evolutionarily and functionally conserved across multiple species, including mice and humans, making animal models invaluable tools for understanding the mechanisms underlying human diseases caused by Fox genes.…”

“…5D). Foxc1 has been implicated in ocular and cerebellar malformations in human patients, as well as in vascular malformations in mice (Kume et al, 2001;Kume, 2009;Delahaye et al, 2012;Haldipur et al, 2014).…”

FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1

“…FOXC1 is a member of the forkhead family of transcription factors (which includes FOXA1/ A2) that act as pioneer transcription factors that are essential for hepatic specification (Lee et al 2005;Zaret and Carroll 2011). FOXC1 has been implicated in growth of cerebellum (Haldipur et al 2014) and corneal vascular development (Seo et al 2012). Finally, SOX9 is an HMGbox transcription factor that has been implicated in regulating development of various stem cell compartments, including the liver (Jo et al 2014).…”

Endothelial cell specification in the somite is compromised in Pax3-positive progenitors of Foxc1/2 conditional mutants, with loss of forelimb myogenesis

“…It remains to be seen how this effect is mediated; presumably, it occurs via signalling to myogenic progenitors by endothelial cells, necessary for their migration. Foxc1 in mesenchymal cells in the developing cerebellum has been shown to directly activate the gene that encodes Sdf1α (Cxcl12 -Mouse Genome Informatics) (Zarbalis et al, 2012), the ligand of Cxcr4, with major consequences for radial glial cell organisation and neuronal migration via Cxcr4 signalling in the absence of Foxc1 (Haldipur et al, 2014). Cxcr4 is expressed on myogenic progenitor cells that migrate to the limb and, in its absence, migration of a subset of progenitors is compromised and some limb muscles are missing (Vasyutina et al, 2005).…”