title: NPC1 gene deficiency leads to lack of neural stem cell self-renewal and abnormal differentiation through activation of p38 mitogen-activated protein kinase signaling.
abstract: 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.
authors.affiliation: 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.
authors.forename: Se-Ran
authors.initials: SR
authors.lastname: Yang
authors.forename: Sun-Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Kyoung-Hee
authors.initials: KH
authors.lastname: Byun
authors.forename: Brian
authors.initials: B
authors.lastname: Hutchinson
authors.forename: Bong-Hee
authors.initials: BH
authors.lastname: Lee
authors.forename: Makoto
authors.initials: M
authors.lastname: Michikawa
authors.forename: Yong-Soon
authors.initials: YS
authors.lastname: Lee
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Kang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology; D002454:Cell Differentiation; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008954:Models, Biological; D009474:Neurons / Q000502:physiology*; D000077296:Niemann-Pick C1 Protein; D009930:Organic Chemicals / Q000494:pharmacology; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051881:Receptor, Notch1; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D009930:Organic Chemicals; C466090:PD 98058; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D051881:Receptor, Notch1; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole