spacer gif spacer gif spacer gif spacer gif ARCHIVE ANNOUNCEMENT! spacer gif
QUICK SEARCH:   [advanced]


spacer gif
     Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents    

First published online 12 October 2005
doi: 10.1242/dev.02079

Development 132, 5115-5124 (2005)
Published by The Company of Biologists 2005
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrowOA All Versions of this Article:
dev.02079v1
132/22/5115    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Huang, X.
Right arrow Articles by Scott, M. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Huang, X.
Right arrow Articles by Scott, M. P.

A Drosophila model of the Niemann-Pick type C lysosome storage disease: dnpc1a is required for molting and sterol homeostasis

Xun Huang1, Kaye Suyama1, JoAnn Buchanan2, Alan J. Zhu1 and Matthew P. Scott1,*

1 Departments of Developmental Biology, Genetics, and Bioengineering, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5439, USA
2 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5439, USA

* Author for correspondence (e-mail: scott{at}cmgm.stanford.edu)

Accepted 8 September 2005

Niemann-Pick type C (NPC) disease is a fatal autosomal-recessive neurodegenerative disorder characterized by the inappropriate accumulation of unesterified cholesterol in aberrant organelles. The disease is due to mutations in either of two genes, NPC1, which encodes a transmembrane protein related to the Hedgehog receptor Patched, and NPC2, which encodes a secreted cholesterol-binding protein. Npc1 mutant mice can be partially rescued by treatment with specific steroids. We have created a Drosophila NPC model by mutating dnpc1a, one of two Drosophila genes related to mammalian NPC1. Cells throughout the bodies of dnpc1a mutants accumulated sterol in a punctate pattern, as in individuals with NPC1 mutations. The mutants developed only to the first larval stage and were unable to molt. Molting after the normal first instar period was restored to various degrees by feeding the mutants the steroid molting hormone 20-hydroxyecdysone, or the precursors of ecdysone biosynthesis, cholesterol and 7-dehydrocholesterol. dnpc1a is normally highly expressed in the ecdysone-producing ring gland. Ring gland-specific expression of dnpc1a in otherwise mutant flies allowed development to adulthood, suggesting that the lack of ecdysone in the mutants is the cause of death. We propose that dnpc1a mutants have sterols trapped in aberrant organelles, leading to a shortage of sterol in the endoplasmic reticulum and/or mitochondria of ring gland cells, and, consequently, inadequate ecdysone synthesis.

Key words: Niemann-Pick Type C, Sterol, Steroid, Ecdysone, Drosophila, Lysosome storage




This article has been cited by other articles:


Home page
 Genes Dev.Home page
D. D. Kaplan, G. Zimmermann, K. Suyama, T. Meyer, and M. P. Scott
A nucleostemin family GTPase, NS3, acts in serotonergic neurons to regulate insulin signaling and control body size
Genes & Dev., July 15, 2008; 22(14): 1877 - 1893.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
S. E. Phillips, E. A. Woodruff III, P. Liang, M. Patten, and K. Broadie
Neuronal Loss of Drosophila NPC1a Causes Cholesterol Aggregation and Age-Progressive Neurodegeneration
J. Neurosci., June 25, 2008; 28(26): 6569 - 6582.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
A. Talamillo, J. Sanchez, R. Cantera, C. Perez, D. Martin, E. Caminero, and R. Barrio
Smt3 is required for Drosophila melanogaster metamorphosis
Development, May 1, 2008; 135(9): 1659 - 1668.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
X. Huang, J. T. Warren, J. Buchanan, L. I. Gilbert, and M. P. Scott
Drosophila Niemann-Pick Type C-2 genes control sterol homeostasis and steroid biosynthesis: a model of human neurodegenerative disease
Development, October 15, 2007; 134(20): 3733 - 3742.
[Abstract] [Full Text] [PDF]

Home page
 DevelopmentHome page
T. Yoshiyama, T. Namiki, K. Mita, H. Kataoka, and R. Niwa
Neverland is an evolutionally conserved Rieske-domain protein that is essential for ecdysone synthesis and insect growth
Development, July 1, 2006; 133(13): 2565 - 2574.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
C. Xie, J. A. Richardson, S. D. Turley, and J. M. Dietschy
Cholesterol substrate pools and steroid hormone levels are normal in the face of mutational inactivation of NPC1 protein
J. Lipid Res., May 1, 2006; 47(5): 953 - 963.
[Abstract] [Full Text] [PDF]

Home page
 GeneticsHome page
A. J. Hickey, H. L. Chotkowski, N. Singh, J. G. Ault, C. A. Korey, M. E. MacDonald, and R. L. Glaser
Palmitoyl-Protein Thioesterase 1 Deficiency in Drosophila melanogaster Causes Accumulation of Abnormal Storage Material and Reduced Life Span
Genetics, April 1, 2006; 172(4): 2379 - 2390.
[Abstract] [Full Text] [PDF]


© The Company of Biologists Ltd 2005