Skeletal patterning begins during embryogenesis when mesenchymal stem cells (MSC) condensate into elements that prefigure the future bone. Formation of the embryologic skeleton proceeds through a complex process of both endochondral and intramembranous ossification. During intramembranous ossification and postnatal skeletal formation, the mesenchyamal stem cells give rise to osteoblasts, which synthesize the matrix constituents on bone forming surfaces. Following the initial commitment to the osteoblast lineage, the osteoprogenitor cells continues to proliferate and proceed through a series of developmental stages that culminate in the generation of the mature osteoblast that is responsible for synthesizing extracellular matrix. Proliferation, differentiation and bone remodeling activities of osteoblasts involve a complex temporal network of growth factors, signaling proteins, and transcription factors, of which many have yet to be identified. The broad objectives of this project are to expand our understanding of the transcriptional and signaling mechanisms that govern the differentiation and activation of osteoblasts during skeletal formation and remodeling. The candidate's proposal focuses on the regulation of WWP1 in osteoblast biology by building upon the candidates recent finding that identified the zinc-finger adapter protein Schnurri-3 (Shn3) as an essential regulator of osteoblast synthetic acitivity through its interaction with WWP1. The candidate has taken an unbiased approach to identify novel regulators of osteoblast differentiation from mesechymal stem cells. Conducting the mentored phase of the project in the laboratory of Dr. Laurie Glimcher will provide an ideal environment to develop the foundation necessary for continuing to research the molecular events that govern the process of bone remodeling during the independent phase in the candidates own academic lab. Relevance: Functional deregulation of osteoblasts affects bone mass and contributes to the pathogenesis of skeletal disorders, including osteoporosis, erosive arthritis and primary and metastatic bone malignancies. As the population in the United States ages, the incidence of these diseases will increase and present an expanding source of morbidity and mortality. A complete molecular understanding of osteoblast biology will provide for better therapeutic targets to help protect and possibly restore those tissue that have been compromised during the these various skeletal disorders.
| Singh, Anju; Lester, Chantel; Drapp, Rebecca et al. (2015) Tetraspanin CD9 and ectonucleotidase CD73 identify an osteochondroprogenitor population with elevated osteogenic properties. Development 142:438-43 |
| Zou, Weiguo; Greenblatt, Matthew B; Brady, Nicholas et al. (2013) The microtubule-associated protein DCAMKL1 regulates osteoblast function via repression of Runx2. J Exp Med 210:1793-806 |
| Shim, Jae-Hyuck; Greenblatt, Matthew B; Zou, Weiguo et al. (2013) Schnurri-3 regulates ERK downstream of WNT signaling in osteoblasts. J Clin Invest 123:4010-22 |
| Wein, Marc N; Jones, Dallas C; Shim, Jae-Hyuck et al. (2012) Control of bone resorption in mice by Schnurri-3. Proc Natl Acad Sci U S A 109:8173-8 |
| Staton, Tracy L; Lazarevic, Vanja; Jones, Dallas C et al. (2011) Dampening of death pathways by schnurri-2 is essential for T-cell development. Nature 472:105-9 |
| Jones, Dallas; Glimcher, Laurie H; Aliprantis, Antonios O (2011) Osteoimmunology at the nexus of arthritis, osteoporosis, cancer, and infection. J Clin Invest 121:2534-42 |
| Zou, Weiguo; Greenblatt, Matthew B; Shim, Jae-Hyuck et al. (2011) MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice. J Clin Invest 121:4383-92 |
| Zou, Weiguo; Chen, Xi; Shim, Jae-Hyuck et al. (2011) The E3 ubiquitin ligase Wwp2 regulates craniofacial development through mono-ubiquitylation of Goosecoid. Nat Cell Biol 13:59-65 |
| Jones, Dallas C; Schweitzer, Michelle N; Wein, Marc et al. (2010) Uncoupling of growth plate maturation and bone formation in mice lacking both Schnurri-2 and Schnurri-3. Proc Natl Acad Sci U S A 107:8254-8 |
