Abstract
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.
Highlights
Using constitutively active form of Raf (ca-Raf) transduction, we showed that Neural stem cells (NSCs) in which the Raf-Erk signal is constitutively activated become neurons
The neurogenesis promoted in those studies occurred at relatively low concentrations of FGF2 and in NSC cultures plated at low cell densities compared to those in the more common studies demonstrating FGF2-induced NSC proliferation
In addition to the main Ras-Raf-Erk signal, previous studies showed that FGF2 treatment activated intracellular CREB signaling via an FGF2-inducible CREB kinase or other pathways, and that CREB activation might be responsible for the neuronal differentiation induced by FGF2 treatment[28,29]
Summary
NSC proliferation is inhibited by differentiation stimuli[15,16,17]. Neuronal vs astrocytic differentiation occurs at the expense of the other during brain development[18,19]. Proliferation vs differentiation and neuronal vs astrocytic differentiation are regarded as opposing NSC behaviors. How Raf-Erk signaling triggers the multiple and opposing NSC behaviors is not known. The aim of this study was to address this issue and obtain clues as to how to differentially manipulate NSC behavior. We show here that Raf-Erk activation in NSCs intrinsically promotes neuron differentiation, whereas it causes NSC proliferation and astrocytic differentiation in a paracrine/autocrine manner. Factors released from NSCs upon Raf-Erk activation induce the formation of proliferating RGC-like astrocytes, which can participate in the brain regeneration process. The information obtained furthers our understanding of brain development and aids in regenerative medicine
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