Vascular Endothelial Growth Factor Receptor 3 Controls Neural Stem Cell Activation in Mice and Humans

Jinah Han (1) , Charles-Félix Calvo (2) , Tae hyuk Kang (3) , Kasey l. Baker (1) , June-Hee Park (3) , Carlos Parras (2) , Marine Levittas (2) , Ulrick Birba (2) , Laurence Pibouin-Fragner (1) , Pascal Fragner (1) , Kaya Bilguvar (4) , Ronald s. Duman (5) , Harri Nurmi (6) , Kari Alitalo (6) , Anne c. Eichmann (1) , Jean-Léon Thomas (2, 3)

1 YSM - Yale School of Medicine [New Haven, Connecticut]
2 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
3 Department of Neurology
4 Department of Genetics
5 Department of Psychiatry
6 Wihuri Research Institute [Helsinki, Finland]

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.

Domains: Cellular Biology; Genetics

Jinah Han, Charles-Félix Calvo, Tae hyuk Kang, Kasey l. Baker, June-Hee Park, et al.. Vascular Endothelial Growth Factor Receptor 3 Controls Neural Stem Cell Activation in Mice and Humans. Cell Reports, 2015, 10 (7), pp.1158-1172. ⟨10.1016/j.celrep.2015.01.049⟩. ⟨hal-01213839⟩