Daniel S. Greenspan, Ph.D. Professor Research Department of Pathology and Laboratory Medicine, Pharmacology dsgreens@wisc.edu

Research Description:

Our research is currently focused on several classes of extracellular regulatory molecules that play key roles in vertebrate and invertebrate development and homeostasis. One class of these regulatory molecules is composed of a small family of proteases that appear key to the biosynthetic processing of a number of structural proteins and enzymes from precursor molecules to their mature functional forms. Examples of this first class of molecules are Tolloid, in Drosophila, and the mammalian proteases, discovered and characterized in this lab, Bone Morphogenetic Protein-1 (BMP-1), mammalian Tolloid (mTLD) and mammalian Tolloid-like 1 and 2 (mTLL-1 and mTLL-2). Another class of regulatory molecules under study in the lab comprises antagonists of signaling by the bone morphogenetic protein subset of transforming growth Factor-b (TGF-b)-like growth factors. An example of the latter class of regulatory molecules is the protein Chordin. Two additional classes of regulatory molecules modify the actions of the first two by, as yet, unclear mechanisms. Examples of the latter class of molecules are twisted gastrulation (TSG) and procollagen C-proteinase enhancers 1 and 2 (PCPE 1 and PCPE 2). Interactions between the various regulatory molecules listed above and other proteins appear to orchestrate the deposition of extracellular matrix with growth factor signaling in morphogenetic processes and in the remodeling of tissues in the adult (e.g. wound healing, bone remodeling and synaptic plasticity associated with learning). Our studies employ biochemical, genetic and developmental analyses. Such studies include the production of recombinant versions of proteins of interest for in vitro and cell culture assays of protein function; the production, characterization and intercrossing of "knockout" mice that have altered alleles for the genes of interest; and examination of possible links between defects in the genes we study and human diseases. A final facet of what we are doing involves collaborative interactions with biotechnology companies seeking to develop inhibitors of some of the proteases that we study. Such inhibitors are of potential use in therapeutic interventions for treatment of fibrotic conditions and certain types of cancer.

The figure shows the targeting vector (A) and molecular analyses (B-D) used in the creation of "knockout" mice that showed mTLL-1 to be necessary for correct positioning and formation of the mammalian heart. Homozygous null embryos (E) die at day 13.5 of gestation, due to a spectrum of cardiac-specific defects. A wild type littermate is shown for comparison (F).

Selected Publications: Articles on PubMed

• Ge G, Fernández C A, Moses MA, and Greenspan DS. (2007). Bone morphogenetic protein 1 processes prolactin to a 17-kDa anti-angiogenic factor. PNAS USA. 104:10010-10015.

• Jasuja R, Ge G, Voss NG, Lyman-Gengerich J, Branam AM, Pelegri FJ, and Greenspan DS. (2007). Bone morphogenetic protein  prodomain specifically binds and regulates signaling of bone morphogenetic proteins 2 and 4. J Biol Chem. 282:9053-9062.

• Hopkins DR, Keles S, and Greenspan DS. (2007). The bone morphogenetic protein 1/Tolloid-like metalloproteinases. Matrix Biol. 26:508-523.

• Zhang Y, Ge G, and Greenspan DS. (2006). Inhibition of bone morphogenetic protein 1 by native and altered forms of a2-macroglobulin. J Biol Chem. 281:39096-39104.

• Ge G and Greenspan DS. (2006). BMP1 Controls TGFb1 Activation Via Cleavage of Latent TGFb-binding Protein. J Cell Biol. 175:111-120.

• Jasuja R, Voss N, Ge G, Hoffman GG, Lyman-Gingerich J, Pelegri F, and Greenspan DS. (2006). bmp1 and mini fin are functionally redundant in regulating formation of the zebrafish dorsoventral axis. Mech Dev. 123:548-558.

• Steiglitz BM,  Kreider JM, Frankenburg EP, Pappano WN, Hoffman GG, Meganck, JA, Liang X, Höök M, Birk DE, Goldstein SA, and Greenspan DS. (2006). 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.

• Ge G, Zhang Y, Steiglitz BM, and Greenspan DS. (2006). Mammalian tolloid-like 1 binds procollagen C-proteinase enhancer 1 and differs from bone morphogenetic protein 1 in the functional roles of homologous protein domains. J Biol Chem. 281:10786-10798.

• Ge G, Hopkins DR, Ho W-B, and Greenspan DS. (2005). GDF11 forms a BMP1-activated latent complex that can modulate nerve growth factor-induced differentiation of PC12 cells. Mol Cell Biol. 25:5846-5858.

• Scott IC, Blitz IL, Pappano WN, Maas SA, Cho KWY, and Greenspan DS. (2001). Twisted gastrulation homologs are extracellular cofactors in antagonism of BMP signaling. Nature. 410:475-478. (See News and Views Nature. 410:423-424)

Postdoctoral and Graduate Student positions are available immediately.

Graduate Research Assistants:

• Amanda Branam
• Delana Hopkins
• Lisa Zhang

Research Specialist: Guy Hoffman

Postdoctoral Fellow: Guorui Huang PhD

Past lab members:

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