Syndecans, cell surface heparan sulfate proteoglycans, (HSPG) bind and modulate the activity of a large number of extra-cellular effectors. The ectodomains of the syndecans can be shed, generating soluble HSPGs that can inhibit these cell surface interactions. Several transgenic mouse lines that express high levels of cell surface syndecan- 1 under the control of a CMV promoter/enhancer were generated to evaluate its functions in vivo. Syndecan- 1 was expressed in multiple somatic tissues and in the hypothalamic areas that regulate body weight. The transgenic mice mimic (i) obese mice with abnormalities in melanocortin-4 receptor function and (ii) humans with the Bardet-Biedl syndrome, a genetic malformation and obesity syndrome of unknown etiology. Transgenic expression of syndecan- 1 appears to have has uncovered a physiological control of feeding behavior. These studies define new functions for syndecans and have important implications for understanding eating disorders, both obesity and cachexia. Obesity is a significant public health hazard; about half of U.S. women and men are now considered overweight and the IOM indicates that this costs more than $70 billion annually in the U.S. Thus, syndecan induction and syndecan interactions are potentially important new targets for pharmacological control of body weight. Specifically, the investigators aim to explore the remarkable phenotypes produced by syndecan- 1 overexpression: (i) establish the role of syndecans in melanocortin receptor function by characterizing the interaction of syndecans with agouti/AGRP peptides and analyzing how this interaction modulates melanocortin receptor signaling both in vitro and in vivo. (ii) evaluate whether hypothalamic expression of syndecan-3 is a physiological regulator of feeding behavior by characterizing the induced expression of hypothalamic syndecan-3. analyzing feeding behavior in syndecan-3 null mice and identifying potential regulators of hypothalamic synce~an-3 expression. (iii) analyze the obesity and morphogenetic abnormalities of the syndecan- 1 overexpressing mouse by evaluating the mouse as a genetic model of the Bardet-Biedl syndrome and by identifying the genes responsible for morphogenetic abnormalities and for reducing the obesity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD006763-26A1
Application #
6054708
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Grave, Gilman D
Project Start
2000-03-01
Project End
2005-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
26
Fiscal Year
2000
Total Cost
$362,718
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Reizes, Ofer; Goldberger, Olga; Smith, April C et al. (2006) Insulin promotes shedding of syndecan ectodomains from 3T3-L1 adipocytes: a proposed mechanism for stabilization of extracellular lipoprotein lipase. Biochemistry 45:5703-11
Ueno, M; Yamada, S; Zako, M et al. (2001) Structural characterization of heparan sulfate and chondroitin sulfate of syndecan-1 purified from normal murine mammary gland epithelial cells. Common phosphorylation of xylose and differential sulfation of galactose in the protein linkage region tetrasa J Biol Chem 276:29134-40
Reizes, O; Lincecum, J; Wang, Z et al. (2001) Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3. Cell 106:105-16
Park, P W; Reizes, O; Bernfield, M (2000) Cell surface heparan sulfate proteoglycans: selective regulators of ligand-receptor encounters. J Biol Chem 275:29923-6
Sun, D; Mcalmon, K R; Davies, J A et al. (1998) Simultaneous loss of expression of syndecan-1 and E-cadherin in the embryonic palate during epithelial-mesenchymal transformation. Int J Dev Biol 42:733-6
Kato, M; Wang, H; Kainulainen, V et al. (1998) Physiological degradation converts the soluble syndecan-1 ectodomain from an inhibitor to a potent activator of FGF-2. Nat Med 4:691-7
Cook, D M; Hinkes, M T; Bernfield, M et al. (1996) Transcriptional activation of the syndecan-1 promoter by the Wilms' tumor protein WT1. Oncogene 13:1789-99
Kokenyesi, R; Bernfield, M (1994) Core protein structure and sequence determine the site and presence of heparan sulfate and chondroitin sulfate on syndecan-1. J Biol Chem 269:12304-9
Spring, J; Paine-Saunders, S E; Hynes, R O et al. (1994) Drosophila syndecan: conservation of a cell-surface heparan sulfate proteoglycan. Proc Natl Acad Sci U S A 91:3334-8
Neumann, P E; Frankel, W N; Letts, V A et al. (1994) Multifactorial inheritance of neural tube defects: localization of the major gene and recognition of modifiers in ct mutant mice. Nat Genet 6:357-62

Showing the most recent 10 out of 40 publications