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TISSUE-SPECIFIC STEM CELLS

NPC1 Gene Deficiency Leads to Lack of Neural Stem Cell Self-Renewal and Abnormal Differentiation Through Activation of p38 Mitogen-Activated Protein Kinase Signaling

^a Laboratory of Stem Cell and Tumor Biology, Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul, Korea;
^b Department of Anatomy and Neurobiology, College of Medicine, Cheju National University, Cheju, Korea;
^c Department of Alzheimer’s Disease Research, National Institute for Longevity Sciences, Morioka, Obu, Aichi, Japan

Key Words. Neural stem cells • Astrocytes • Niemann-Pick type C1 • p38 mitogen-activated protein kinase

Correspondence: Kyung-Sun Kang, D.V.M., Ph.D., Laboratory of Stem Cell and Tumor Biology, Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, SAN 56-1, Sillim-Dong, Kwanak-gu, Seoul 151-742, Korea. Telephone 82-2-880-1246; Fax: 82-2-876-7610; e-mail: kangpub{at}snu.ac.kr

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 self-renewal ability of NSCs, as well as the differentiation. NSCs from NPC1^–/– mice showed impaired self-renewal ability compared with the NPC1^+/+ 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 self-renewal ability of NSCs from NPC^–/– mice. This indicated that the NPC1 deficiency can lead to lack of self-renewal and altered differentiation of NSCs mediated by the activation of p38 MAPK, impairing the generation of neurospheres from NPC1^–/– Thus, the NPC1 gene may play a crucial role in NSC self-renewal associated with p38 MAPK.