Cell autonomous Vegf-C/Vegfr3 signaling in adult neural stem cells

In the adult mammalian brain, the potential to generate new neurons is restricted to a limited number of sites, called neurogenic niches, which are mainly the subventricular zone lining the cerebral ventricles and the dentate gyrus of the hippocampus. Neurogenic niches harbor a unique population of neural stem cells (NSCs), self-renewing cells with hallmarks of astrocytes that generate neurons and glia. Brain injury in humans as a result of trauma, hypoxia or neuron-glial pathologies activates neurogenesis in these niches, attesting to an endogenous repair potential that is, however, generally not sufficient to allow complete rescue of lost tissues. To safely enhance this endogenous neurogenic response, it is crucial to characterize mechanisms controling NSCs in their niche. NSCs are predominantly found in a quiescent state but can be activated to either self-renew or generate neural progenitors cells (NPCs). Understanding NSC activation mechanisms is a major goal in NSC biology and a variety of synergetic and antagonistic factors have been shown to dynamically regulate NSCs in each neurogenic niche [1]. The majority of signals originate from NSC-neighboring cells such as ependymal, endothelial, microglial or neuronal cells [2]. However, adult NSCs themselves also contribute to NSC activation and niche homeostasis through autocrine signaling [1]. We and others have recently underscored a specific role for Vascular endothelial growth factors (Vegfs) in these processes [3-6]. Our studies have focused on the expression and role of Vegf-C, the main lymphangiogenic factor, and Vegfr3, the high affinity receptor of Vegf-C, in adult neurogenic niches [4, 5]. First, we found that Vegf-C displays an enriched expression in NSCs compared to neighboring cells of adult niches. Similarly, Vegfr3 is expressed by NSCs while its expression declines in NPC progeny. Second, conditional Vegfr3 deletion in NSC, using the Glast CreERT2 ; Vegfr3 lox mouse model, decreases the number of dividing NSCs/NPCs and newborn neurons, without affecting the pool of NSCs. Vegfr3 activity is therefore not necessary for NSC maintenance, but is required for the generation of progenitors and neuroblasts. Third, in vitro and in vivo approaches revealed that Vegf-C treatment increased the number of dividing cells in cultured NSCs and neurogenic niches, respectively. In contrast to Vegf-A [7], another closely related vascular growth factor expressed in neurogenic niches, Vegf-C activates NSCs without inducing vascular proliferation. Thus, Vegf-C may function more specifically as an activator of NSCs in neurogenic niches. Using transgenic Vegfr3 YFP reporter mice that allow isolation of Vegfr3-expressing …