Neural stem cells (NSCs) are capable of giving rise to neurons, glia, and astrocytes. Although self-renewal and differentiation in NSCs are regulated by many genes, such as Notch and Numb, little is known about the role of defective genes on the self-renewal and differentiation of NSCs from developing brain. The Niemann-Pick type C1 (NPC1) disease is a neurodegenerative disease caused by a mutation of the NPC1 gene that affects the function of the NPC1 protein. The ability of NSC self-renewal and differentiation was investigated using a model of NPC1 disease. The NPC1 disorder significantly affected the selfrenewal ability of NSCs, as well as the differentiation. NSCs from NPC1Ϫ/Ϫ mice showed impaired self-renewal ability compared with the NPC1 ϩ/ϩ mice. These alterations were accompanied by the enhanced activity of p38 mitogen-activated protein kinases (MAPKs). Further, the specific p38 MAPK inhibitor SB202190 improved the selfrenewal ability of NSCs from NPC Ϫ/Ϫ mice. This indicated that the NPC1 deficiency can lead to lack of selfrenewal and altered differentiation of NSCs mediated by the activation of p38 MAPK, impairing the generation of neurospheres from NPC1 Ϫ/Ϫ . Thus, the NPC1 gene may play a crucial role in NSC self-renewal associated with p38 MAPK. STEM CELLS 2006;24:292-298

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