Matrix-Binding Vascular Endothelial Growth Factor (VEGF) Isoforms Guide Granule Cell Migration in the Cerebellum via VEGF Receptor Flk1

Abstract

Vascular endothelial growth factor (VEGF) regulates angiogenesis, but also has important, yet poorly characterized roles in neuronal wiring. Using several genetic and in vitro approaches, we discovered a novel role for VEGF in the control of cerebellar granule cell (GC) migration from the external granule cell layer (EGL) toward the Purkinje cell layer (PCL). GCs express the VEGF receptor Flk1, and are chemoattracted by VEGF, whose levels are higher in the PCL than EGL. Lowering VEGF levels in mice in vivo or ectopic VEGF expression in the EGL ex vivo perturbs GC migration. Using GC-specific Flk1 knock-out mice, we provide for the first time in vivo evidence for a direct chemoattractive effect of VEGF on neurons via Flk1 signaling. Finally, using knock-in mice expressing single VEGF isoforms, we show that pericellular deposition of matrix-bound VEGF isoforms around PC dendrites is necessary for proper GC migration in vivo. These findings identify a previously unknown role for VEGF in neuronal migration.

Astrocytes Control the Development of the Migration-Promoting Vasculature Scaffold in the Postnatal Brain via VEGF Signaling

“…) (data not shown). In agreement with our data, it has been previously demonstrated that VEGF in the cortex and cerebellum is expressed by cortical neurons and Purkinje cells, respectively (Ogunshola et al, 2002;Ruiz de Almodovar et al, 2010). This differential expression pattern of VEGF may explain the different effects of conditioning medium derived from cultures of astrocytes from P3 SVZ, cortex, cerebellum, and adult SVZ on BV development and growth (Fig.…”

“…Recently, it has been demonstrated also that Purkinje cell-derived VEGF guides granule cell migration in the cerebellum (Ruiz de Almodovar et al, 2010). However, the role of VEGF in neuroblast migration in the adult RMS remains controversial (Wittko et al, 2009;Licht et al, 2010).…”

VEGF modulates NMDA receptors activity in cerebellar granule cells through Src-family kinases before synapse formation

“…They stimulate neurogenesis, long-term potentiation, and learning, whereas low VEGF levels cause or aggravate motoneuron degeneration, and VEGF delivery delays paralysis in preclinical models (1). During cerebellar development, VEGF chemoattracts granule cells (GCs) from the external GC layer (EGL) toward the internal GC layer (IGL) (2). This chemotactic activity of VEGF for GCs in vivo is mediated by direct activation of Flk1 in GCs, independently of its angiogenic activity (2).…”

“…During cerebellar development, VEGF chemoattracts granule cells (GCs) from the external GC layer (EGL) toward the internal GC layer (IGL) (2). This chemotactic activity of VEGF for GCs in vivo is mediated by direct activation of Flk1 in GCs, independently of its angiogenic activity (2). However, the mechanisms via which VEGF regulates GC migration in the cerebellum remain unknown.…”

Molecular Parallels between Neural and Vascular Development

“…In the neonatal cerebellum, the granule cells migrate radially from the external granular layer (EGL), which expresses low levels of VEGF-A toward the Purkinje cell layer (PCL), where high levels of matrix-bound VEGF-A isoforms are deposited around the dendrites of Purkinje cells. Granule-cell-specific Vegfr-2 knockout mice provided in vivo evidence for a direct chemo-attractive effect of VEGF on neurons via VEGFR-2 signaling (Ruiz de Almodovar et al 2010).…”