Impaired motor coordination and disrupted cerebellar architecture in Fgfr1 and Fgfr2 double knockout mice

Fibroblast growth factor receptor (FGFR) signaling determines the size of the cerebral cortex by regulating the amplification of radial glial stem cells, and participates in the formation of midline glial structures. We show that Fgfr1 and Fgfr2 double knockouts (FGFR DKO) generated by Cre-mediated recombination driven by the human GFAP promoter (hGFAP) have reduced cerebellar size due to reduced proliferation of radial glia and other glial precursors in late embryonic and neonatal FGFR DKO mice. The proliferation of granule cell progenitors (GCPs) in the EGL was also reduced, leading to reduced granule cell numbers. Furthermore, both inward migration of granule cells into the inner granule cell layer (IGL) and outward migration of GABA interneurons into the molecular layer (ML) were arrested, disrupting layer and lobular morphology. Purkinje neurons and their dendrites, which were not targeted by Cre-mediated recombination of Fgf receptors, were also misplaced in FGFR DKO mice, possibly as a consequence of altered Bergmann glia orientation or reduced granule cell number. Our findings indicate a dual role for FGFR signaling in cerebellar morphogenesis. The first role is to amplify the number of granule neuron precursors in the external granular layer and glial precursor cells throughout the cerebellum. The second is to establish the correct Bergmann glia morphology, which is crucial for granule cell migration. The disrupted cerebellar size and laminar architecture resulting from loss of FGFR signaling impair motor learning and coordination in FGFR DKO mice.

► Fgfr1 and Fgfr2 double knockout mice (FGFR DKO) have greatly reduced cerebellar size and decreased granule cell numbers. ► FGFR DKO have reduced proliferation of glial precursors and granule cell precursors. ► Granule cell and interneuron migration was arrested in FGR DKO, disrupting layer morphology and misplacing Purkinje neurons. ► The disrupted cerebellar size and laminar architecture impairs motor learning and coordination in FGFR DKO mice.