Daniel S. Greenspan
Ph.D., New York University, 1981
Postdoctoral Research: Yale University
Lab website: http://www.crb.wisc.edu/faculty/Greenspan.asp
Address: Room 4503 WIMRII, 1111 Highland Ave.
Department: Cell and Regenerative Biology
Genes important to vertebrate development and human disease
Human and Mammalian
Our research focuses on extracellular regulatory proteins that control and orchestrate events as diverse as growth factor signaling and formation of the extracellular matrix (ECM). Such events are critical in adult vertebrates (e.g. for maintenance of the cardiovascular system, wound healing, turnover of the skeleton and synaptic plasticity) and are even more dynamic during development. One class of these regulatory molecules comprises small families of proteases that activate and inactivate various growth factors, enzymes and extracellular structural macromolecules. Another class comprises antagonists of signaling by members of the TGFb superfamily of growth factors. Three additional classes of regulatory molecules under study modify actions of the first two by as yet unclear mechanisms. Molecules we study play central roles in morphogenetic processes and defects in these proteins may underlie human disease. Our studies employ biochemical, genetic and developmental analyses, including characterizing standard and conditional “knockout” mice, and zebrafish and examining possible links between defects in genes of interest and human development and disease. Current studies include roles of extracellular proteins in adipocyte biology, pre-diabetic symptoms, atherosclerosis, and organ transplant rejection. The latter two studies include translational studies of human patients.
Muir AM, Ren Y, Hopkins Butz D, Davis NA, Blank RD, Birk DE, Lee S-J, Rowe D, Feng JQ, Greenspan DS. Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. Hum Mol Genet 23, 3085-3101 (2014).
Park AC, Phillips CL, Pfeiffer FM, Roenneburg DS, Kernien JF, Adams SM, Davidson JM,Birk DE, Greenspan DS. Homozygosity and heterozygosity for null Col5a2 alleles produce embryonic lethality and a novel classic Ehlers-Danlos syndrome-related phenotype. Am J
Pathol 185, In press (2015).
Asharani PV, Keupp K, Semler O, Wang W, Li Y, Thiele H, Yigit G, Pohl E, Becker J, Frommolt P, Sonntag C, Altmüller J, Zimmermann K Greenspan DS, Akarsu NA, Netzer C, Schönau E, Wirth R, Hammerschmidt M, Nürnberg P, Wollnik B, Carney TJ. Attenuated BMP1 function compromises Osteogenesis, leading to bone fragility in humans and zebrafish. Am J Hum Genet 90, 661-674 (2012).
Huang G, Greenspan DS. Roles of ECM in the
function of metabolic tissues. Trends
Endocrinol. Metab 23, 16-22
Muir A, Greenspan, DS. Metalloproteinases in Drosophila to humans that are central players in developmental processes. J. Biol. Chem. 286, 41905-41911 (2011).
Kim B, Huang G., Ho W-B, Greenspan DS. Bone morphogenetic protein-1 processes insulin-like growth factor-binding protein 3. J. Biol. Chem. 286, 29014-29025 (2011).
Huang G, Ge G, Wang D, Gopalakrishnan B, Butz DH, Colman RJ, Nagy A, Greenspan DS. a3(V) collagen is critical for glucose homeostasis due to effects in islets and peripheral tissues in mice. J. Clin. Invest. 121, 769-783 (2011).
Dart ML, Jankowska-Gan E, Huang G, Roenneburg DA, Keller M R, Torrealba JR, Rhoads A, Marshall-Case S, Kim B, Bobadilla JL, Haynes LD, Wilkes DS, Burlingham WJ, and Greenspan DS. IL-17-dependent autoimmunity to collagen type V in atherosclerosis. Circ. Res. 107, 1106-1116 (2010).
Branam AM, Hoffman GG, Pelegri F, Greenspan DS. Zebrafish chordin-like and chordin are functionally redundant in regulating patterning of the dorsoventral axis. Dev. Biol. 341, 444-458 (2010).
Huang G, Zhang Y, Kim B, Ge G, Annis DS, Mosher DF, and Greenspan DS. Fibronectin binds and enhances the activity of bone morphogenetic protein 1. J. Biol. Chem. 284, 25879-25888 (2009).
Kobayashi, K, Luo M, Zhang Y, Wilkes DC, Gao G, Grieskamp T, Yamada C, Liu T-C, Huang G, Basson CT, Kispert A, Greenspan DS*, Sato, TN*. Secreted Frizzled Related Protein 2 is a procollagen C-proteinase enhancer with a role in fibrosis associated with myocardial infarction. Nature Cell Biol. 11, 46-55 (2009).
Le Goff C, Morice-Picard F, Dagoneau N, Wang LW, Perrot C, Crow YJ, Bauer F, Flori E, Prost-Squarcioni C, Krakow D, Bonnet D, Ge G, Greenspan DS, Le Merrer M, Munnich A, Apte SS, Cormier-Daire V. ADAMTSL2 mutations in geleophysic dysplasia reveal a role for ADAMTS-like proteins in the regulation of TGFb bioavailability. Nature Genet. 40,1119-1123 (2008).
Ge G, Fernández C A, Moses MA, and Greenspan DS. Bone morphogenetic protein 1 processes prolactin to a 17-kDa anti-angiogenic factor. Proc. Natl. Acad. Sci. U. S. A. 104,10010-10015 (2007).
Jasuja R, Ge G, Voss NG, Lyman-Gengerich J, Branam AM, Pelegri FJ, and Greenspan DS. Bone morphogenetic protein 1 prodomain specifically binds and regulates signaling of bone morphogenetic proteins 2 and 4. J. Biol. Chem. 282, 9053-9062 (2007).
Ge G, and Greenspan DS. BMP1 Controls TGFb1 Activation Via Cleavage of Latent TGFb-binding Protein. J. Cell Biol. 175, 111-120 (2006).
Jasuja R, Voss N, Ge G, Hoffman GG, Lyman-Gingerich J, Pelegri F, and Greenspan DS. bmp1 and mini fin are functionally redundant in regulating formation of the zebrafish dorsoventral axis. Mech. Dev. 123, 548-558 (2006).
Steiglitz BM, Kreider JM, Frankenburg EP, Pappano WN, Hoffman GG, Meganck, JA, Liang X, Höök M, Birk DE, Goldstein SA, and Greenspan DS. Procollagen C-proteinase enhancer 1 genes are important determinants of the mechanical properties and geometry of bone and the ultrastructure of connective tissues. Mol. Cell. Biol. 26, 238-249 (2006).
Jasuja R, Pappano WN, Allen BL, Rapraeger AC, and Greenspan DS. Cell surface heparan sulfate proteoglycans potentiate Chordin’s antagonism of bone morphogenetic protein signaling and are necessary for cellular uptake of Chordin. J. Biol. Chem. 279, 51289-51297(2004).
Pappano WN, Steiglitz BM, Scott IC, Keene DR and Greenspan DS. Use of Bmp1/Tll1 doubly homozygous null mice and proteomics to identify and validate in vivo substrates of BMP-1/Tolloid-like metalloproteinases. Mol. Cell. Biol. 23, 4428-4438 (2003).
Takahara K, Schwarze U, Imamura Y, Hoffman GG, Toriello H, Smith LT, Byers PH, and Greenspan, D.S.: Order of intron removal Influences multiple splice outcomes, including a 2-exon skip, in a COL5A1 acceptor site mutation that results in abnormal pro-a1(V) N-propeptides and Ehlers-Danlos syndrome type I. Am. J. Hum. Genet. 71, 451-465 (2002).
Scott IC, Blitz IL, Pappano WN, Maas SA, Cho KWY, and Greenspan D.S. Twisted gastrulation homologs are extracellular cofactors in antagonism of BMP signaling. Nature 410, 475-478 (2001).
Clark TG, Conway SJ, Scott IC, Labosky PA, Winnier G, Bundy J, Hogan BLM, and Greenspan, D.S.: The mammalian tolloid-like 1 gene, Tll1, is necessary for normal septation and positioning of the heart. Development 126, 2631-2642 (1999).
Toriello HV, Glover TW, Takahara K, Byers P, Miller DE, Higgins JV, and Greenspan DS. A translocation interrupts the COL5A1 gene in a patient with Ehlers-Danlos syndrome and hypomelanosis of Ito. Nature Genet. 13, 361-365 (1996).
Kessler E, Takahara K, Biniaminov L, Brusel M, and Greenspan DS. Bone Morphogenetic Protein-1: the type I procollagen C-proteinase. Science 271, 360-362 (1996).