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Sci Rep. 2016 Aug 24;6:32025. doi: 10.1038/srep32025.

Neural stem cells secrete factors facilitating brain regeneration upon constitutive Raf-Erk activation.

Rhee YH1,2, Yi SH1,2, Kim JY3, Chang MY1,2, Jo AY1,2, Kim J1,2, Park CH2,4,5, Cho JY6, Choi YJ7, Sun W3, Lee SH1,2,4.

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Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea.
Hanyang Biomedical Research Institute, Hanyang University, Seoul, Korea.
Department of Anatomy, College of Medicine, Korea University, Seoul, Korea.
Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.
Department of Microbiology, College of Medicine, Hanyang University, Seoul, Korea.
Department of Biochemistry, BK21 PLUS Program for Creative Veterinary Science Research and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
ProtAnBio, Co., Seoul, South Korea.


The intracellular Raf-Erk signaling pathway is activated during neural stem cell (NSC) proliferation, and neuronal and astrocytic differentiation. A key question is how this signal can evoke multiple and even opposing NSC behaviors. We show here, using a constitutively active Raf (ca-Raf), that Raf-Erk activation in NSCs induces neuronal differentiation in a cell-autonomous manner. By contrast, it causes NSC proliferation and the formation of astrocytes in an extrinsic autocrine/paracrine manner. Thus, treatment of NSCs with medium (CM) conditioned in ca-Raf-transduced NSCs (Raf-CM; RCM) became activated to form proliferating astrocytes resembling radial glial cells (RGCs) or adult-type NSCs. Infusion of Raf-CM into injured mouse brains caused expansion of the NSC population in the subventricular zone, followed by the formation of new neurons that migrated to the damaged site. Our study shows an example how molecular mechanisms dissecting NSC behaviors can be utilized to develop regenerative therapies in brain disorders.

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