Document Detail


Requirement of Npc1 and availability of cholesterol for early embryonic cell movements in zebrafish.
MedLine Citation:
PMID:  21576600     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Niemann-Pick disease, type C (NP-C), often associated with Niemann-Pick disease, type C1 (NPC1) mutations, is a cholesterol-storage disorder characterized by cellular lipid accumulation, neurodegeneration, and reduced steroid production. To study NPC1 function in vivo, we cloned zebrafish npc1 and analyzed its gene expression and activity by reducing Npc1 protein with morpholino (MO)-oligonucleotides. Filipin staining in npc1-morphant cells was punctate, suggesting abnormal accumulation of cholesterol. Developmentally, reducing Npc1 did not disrupt early cell fate or survival; however, early morphogenetic movements were delayed, and the actin cytoskeleton network was abnormal. MO-induced defects were rescued with ectopic expression of mouse NPC1, demonstrating functional gene conservation, and by treatments with steroids pregnenolone or dexamethasone, suggesting that reduced steroidogenesis contributed to abnormal cell movements. Cell death was found in anterior tissues of npc1 morphants at later stages, consistent with findings in mammals. Collectively, these studies show that npc1 is required early for proper cell movement and cholesterol localization and later for cell survival.
Authors:
Tyler Schwend; Evyn J Loucks; Diana Snyder; Sara C Ahlgren
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-05-16
Journal Detail:
Title:  Journal of lipid research     Volume:  52     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-13     Completed Date:  2011-10-07     Revised Date:  2014-09-05    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1328-44     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Actins / metabolism
Amino Acid Sequence
Animals
Biological Transport / drug effects,  genetics
Cell Death / drug effects,  genetics
Cell Differentiation / drug effects,  genetics
Cell Movement* / drug effects,  genetics
Cholesterol / metabolism*
Cloning, Molecular
Cytoskeleton / drug effects,  metabolism
Dexamethasone / pharmacology
Embryo, Nonmammalian / cytology*,  drug effects,  metabolism*
Gene Expression Regulation, Developmental / drug effects,  genetics
Gene Knockdown Techniques
Humans
Membrane Proteins / chemistry,  deficiency,  genetics,  metabolism*
Mice
Molecular Sequence Data
Oligonucleotides, Antisense / genetics
Ovum / cytology,  drug effects
Pregnenolone / pharmacology
Protein Structure, Tertiary
Rabbits
Zebrafish / embryology*,  genetics,  metabolism*
Zebrafish Proteins / chemistry,  deficiency,  genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
AA-13596/AA/NIAAA NIH HHS; F31 DE019604/DE/NIDCR NIH HHS; F31 DE019604-01/DE/NIDCR NIH HHS; F31 DE019604-02/DE/NIDCR NIH HHS; F31DE019604/DE/NIDCR NIH HHS; P40 RR-012546/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Actins; 0/Membrane Proteins; 0/NPC1 protein, zebrafish; 0/Oligonucleotides, Antisense; 0/Zebrafish Proteins; 73R90F7MQ8/Pregnenolone; 7S5I7G3JQL/Dexamethasone; 97C5T2UQ7J/Cholesterol
Comments/Corrections

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