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doi:10.1534/genetics.105.046565
A more recent version of this article appeared on January 1, 2006.
REGULAR RESEARCH PAPERS |
Mutations of a Drosophila NPC1 gene confer sterol and ecdysone metabolic defects
Megan L Fluegel 1, Tracey J Parker 1 and Leo J Pallanck 1*
1 University of Washington
* To whom correspondence should be addressed. E-mail: pallanck{at}gs.washington.edu.
Submitted on June 7, 2005
Revised on July 22, 2005
Accepted on 22 July 2005
Many aspects of cholesterol metabolism are well understood, but relatively little is known of the molecular mechanisms by which dietary cholesterol is absorbed by the intestine and trafficked within cells following its acquisition. Previous work indicates that the related NPC1 and NPC1L1 proteins function in these processes, although the mechanisms by which this protein family promotes cholesterol absorption and intracellular trafficking remain unclear. We are using a genetic approach in Drosophila to further explore the functions of the NPC1 gene family. The Drosophila genome encodes two NPC1 homologs designated NPC1a and NPC1b that exhibit 42% and 35% identity to the human NPC1 protein, respectively, and significant but lesser similarity to NPC1L1. We find that the NPC1a gene is ubiquitously expressed and that a null allele of NPC1a confers early larval lethality. The recessive lethal phenotype of NPC1a mutants can be partially rescued by a diet of high cholesterol or by including the insect steroid hormone 20-hydroxyecdysone in the diet. These results suggest that NPC1a is required for efficient trafficking of dietary sterols and that reduced ecdysone production is a major consequence of defective sterol trafficking in Drosophila.
Key Words: NPC1, Niemann-Pick Type C, cholesterol, ecdysone, sterol trafficking
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