ABSTRACT
Neural stem cells (NSCs) continuously produce new neurons within the adult mammalian hippocampus. NSCs are typically quiescent but activated to self-renew or differentiate into neural progenitor cells. The molecular mechanisms of NSC activation remain poorly understood. Here, we show that adult hippocampal NSCs express vascular endothelial growth factor receptor (VEGFR) 3 and its ligand VEGF-C, which activates quiescent NSCs to enter the cell cycle and generate progenitor cells. Hippocampal NSC activation and neurogenesis are impaired by conditional deletion of Vegfr3 in NSCs. Functionally, this is associated with compromised NSC activation in response to VEGF-C and physical activity. In NSCs derived from human embryonic stem cells (hESCs), VEGF-C/VEGFR3 mediates intracellular activation of AKT and ERK pathways that control cell fate and proliferation. These findings identify VEGF-C/VEGFR3 signaling as a specific regulator of NSC activation and neurogenesis in mammals.
Subject(s)
Neural Stem Cells/metabolism , Vascular Endothelial Growth Factor Receptor-3/metabolism , Animals , Cell Differentiation , Cell Proliferation , Cells, Cultured , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Hippocampus/metabolism , Humans , Mice , Mice, Inbred C57BL , Neural Stem Cells/cytology , Neural Stem Cells/drug effects , Neurogenesis/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/genetics , Recombinant Proteins/pharmacology , Signal Transduction , Vascular Endothelial Growth Factor C/genetics , Vascular Endothelial Growth Factor C/metabolism , Vascular Endothelial Growth Factor C/pharmacology , Vascular Endothelial Growth Factor Receptor-3/geneticsABSTRACT
Notch cell interaction mechanism governs cell fate decisions in many different cell contexts throughout the lifetime of all Metazoan species. It links the fate of one cell to that of its neighbors through cell-to-cell contacts, and binding of Notch receptors expressed on one cell to their membrane bound ligands on an adjacent cell. Environmental cues, such as growth factors and extracellular matrix molecules, superimpose a dynamic regulation on this canonical Notch signaling pathway. In this review, we will focus on Notch signaling in the vertebrate vascular and nervous systems and examine its role in angiogenesis, neurogenesis, and neurovascular interactions. We will also highlight the molecular relationships of the Notch pathway with vascular endothelial growth factors (VEGFs) and their high-affinity tyrosine kinase VEGF receptors, key regulators of both angiogenesis and neurogenesis.
