skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Juvenile-onset loss of lipid-raft domains in attractin-deficient mice

Abstract

Mutations at the attractin (Atrn) locus in mice result in altered pigmentation on an agouti background, higher basal metabolic rate and juvenile-onset hypomyelination leading to neurodegeneration, while studies on human immune cells indicate a chemotaxis regulatory function. The underlying biochemical defect remains elusive. In this report we identify a role for attractin in plasma membrane maintenance. In attractin's absence there is a decline in plasma membrane glycolipid-enriched rafts from normal levels at 8 weeks to a complete absence by 24 weeks. The structural integrity of lipid rafts depends upon cholesterol and sphingomyelin, and can be identified by partitioning within of ganglioside GM{sub 1}. Despite a significant fall in cellular cholesterol with maturity, and a lesser fall in both membrane and total cellular GM{sub 1}, these parameters lag behind raft loss, and are normal when hypomyelination/neurodegeneration has already begun thus supporting consequence rather than cause. These findings can be recapitulated in Atrn-deficient cell lines propagated in vitro. Further, signal transduction through complex membrane receptor assemblies is not grossly disturbed despite the complete absence of lipid rafts. We find these results compatible with a role for attractin in plasma membrane maintenance and consistent with the proposal that the juvenile-onset hypomyelination and neurodegenerationmore » represent a defect in attractin-mediated raft-dependent myelin biogenesis.« less

Authors:
 [1];  [2];  [3]
  1. Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115 (United States)
  2. Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853 (United States)
  3. Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115 (United States). E-mail: Jonathan_Duke-Cohan@dfci.harvard.edu
Publication Date:
OSTI Identifier:
20972123
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 313; Journal Issue: 4; Other Information: DOI: 10.1016/j.yexcr.2006.11.018; PII: S0014-4827(06)00484-8; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CHOLESTEROL; IN VITRO; JUVENILES; MICE; MUTATIONS; MYELIN; RECEPTORS

Citation Formats

Azouz, Abdallah, Gunn, Teresa M., and Duke-Cohan, Jonathan S. Juvenile-onset loss of lipid-raft domains in attractin-deficient mice. United States: N. p., 2007. Web. doi:10.1016/j.yexcr.2006.11.018.
Azouz, Abdallah, Gunn, Teresa M., & Duke-Cohan, Jonathan S. Juvenile-onset loss of lipid-raft domains in attractin-deficient mice. United States. doi:10.1016/j.yexcr.2006.11.018.
Azouz, Abdallah, Gunn, Teresa M., and Duke-Cohan, Jonathan S. Thu . "Juvenile-onset loss of lipid-raft domains in attractin-deficient mice". United States. doi:10.1016/j.yexcr.2006.11.018.
@article{osti_20972123,
title = {Juvenile-onset loss of lipid-raft domains in attractin-deficient mice},
author = {Azouz, Abdallah and Gunn, Teresa M. and Duke-Cohan, Jonathan S.},
abstractNote = {Mutations at the attractin (Atrn) locus in mice result in altered pigmentation on an agouti background, higher basal metabolic rate and juvenile-onset hypomyelination leading to neurodegeneration, while studies on human immune cells indicate a chemotaxis regulatory function. The underlying biochemical defect remains elusive. In this report we identify a role for attractin in plasma membrane maintenance. In attractin's absence there is a decline in plasma membrane glycolipid-enriched rafts from normal levels at 8 weeks to a complete absence by 24 weeks. The structural integrity of lipid rafts depends upon cholesterol and sphingomyelin, and can be identified by partitioning within of ganglioside GM{sub 1}. Despite a significant fall in cellular cholesterol with maturity, and a lesser fall in both membrane and total cellular GM{sub 1}, these parameters lag behind raft loss, and are normal when hypomyelination/neurodegeneration has already begun thus supporting consequence rather than cause. These findings can be recapitulated in Atrn-deficient cell lines propagated in vitro. Further, signal transduction through complex membrane receptor assemblies is not grossly disturbed despite the complete absence of lipid rafts. We find these results compatible with a role for attractin in plasma membrane maintenance and consistent with the proposal that the juvenile-onset hypomyelination and neurodegeneration represent a defect in attractin-mediated raft-dependent myelin biogenesis.},
doi = {10.1016/j.yexcr.2006.11.018},
journal = {Experimental Cell Research},
number = 4,
volume = 313,
place = {United States},
year = {Thu Feb 15 00:00:00 EST 2007},
month = {Thu Feb 15 00:00:00 EST 2007}
}
  • Here we demonstrate that conditional deletion of mouse uterine Trp53 (p53d/d), molecularly linked to mTORC1 activation and causally linked to premature uterine senescence and preterm birth, results in aberrant lipid signatures within the heterogeneous cell types of embryo implantation sites on day 8 of pregnancy. In situ nanospray desorption electrospray ionization mass spectrometry imaging (nano-DESI MSI) was used to characterize the molecular speciation of free fatty acids, monoacylglycerols, unmodified and oxidized phosphatidylcholine (PC/Ox-PC), and diacylglycerol (DG) species within implantation sites of p53d/d mice and floxed littermates. Implantation sites from p53d/d mice exhibited distinct spatially resolved changes demonstrating accumulation of DGmore » species, depletion of Ox-PC species, and increase in species with more unsaturated acyl chains, including arachidonic and docosahexaenoic acid. Understanding abnormal changes in the abundance and localization of individual lipid species early in the progression to premature birth is important for discovering novel targets for treatments and diagnosis.« less
  • No abstract prepared.
  • The nanostructures of self-assembling biomaterials have been previously designed to tune the release of growth factors in order to optimize biological repair and regeneration. We report here on the discovery that weakly cohesive peptide nanostructures in terms of intermolecular hydrogen bonding, when combined with low concentrations of osteogenic growth factor, enhance both BMP-2 and Wnt mediated signaling in myoblasts and bone marrow stromal cells, respectively. Conversely, analogous nanostructures with enhanced levels of internal hydrogen bonding and cohesion lead to an overall reduction in BMP-2 signaling. We propose that the mechanism for enhanced growth factor signaling by the nanostructures is relatedmore » to their ability to increase diffusion within membrane lipid rafts. The phenomenon reported here could lead to new nanomedicine strategies to mediate growth factor signaling for translational targets.« less
  • No abstract prepared.
  • Exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs), can lead to chronic inflammation and the development of vascular diseases. Because cell adhesion molecules (CAMs) of the cerebrovascular endothelium regulate infiltration of inflammatory cells into the brain, we have explored the molecular mechanisms by which ortho-substituted polychlorinated biphenyls (PCBs), such as PCB153, can upregulate CAMs in brain endothelial cells. Exposure to PCB153 increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as elevated adhesion of leukocytes to brain endothelial cells. These effects were impeded by inhibitors of EGFR, JAKs, or Src activity. Inmore » addition, pharmacological inhibition of NADPH oxidase or disruption of lipid rafts by cholesterol depleting agents blocked PCB153-induced phosphorylation of JAK and Src kinases and upregulation of CAMs. In contrast, silencing of caveolin-1 by siRNA interference did not affect upregulation of ICAM-1 and VCAM-1 in brain endothelial cells stimulated by PCB153. Results of the present study indicate that lipid raft-dependent NADPH oxidase/JAK/EGFR signaling mechanisms regulate the expression of CAMs in brain endothelial cells and adhesion of leukocytes to endothelial monolayers. Due to its role in leukocyte infiltration, induction of CAMs may contribute to PCB-induced cerebrovascular disorders and neurotoxic effects in the CNS.« less