Jean E. Schwarzbauer
Associate Chair, Department of Molecular Biology
Faculty AssistantMatt Montondo
- Ph.D., Molecular Biology, University of Wisconsin-Madison
- B.S., Chemistry, University of Wisconsin-Milwaukee
Research AreaCell Biology, Development & Cancer
Research FocusExtracellular matrix regulation of cell functions
The extracellular matrix is essential for normal organization and function of all tissues. The matrix network is assembled by cells from secreted glycoproteins and proteoglycans which provide specific environmental signals to control cell morphology, migration, differentiation, and proliferation. Deficiencies in matrix composition and architecture correspond with the onset and progression of major diseases including cancer, atherosclerosis, and arthritis. The overall goal of our research is to determine how tissue-specific variations in matrix structure and organization regulate and modulate cell activities.
One of the major components of extracellular matrix is fibronectin, a large, adhesive glycoprotein. Fibronectin interacts with cells and transmits signals primarily through integrin receptors. Integrins constitute a large family of heterodimeric receptors with specificity for extracellular matrix and cell surface ligands. Multiple integrins can recognize fibronectin and, in so doing, activate cell adhesion, migration, and proliferation. We have developed cell culture-based systems to dissect the morphological and intracellular consequences of cell interactions with different types of fibronectin matrix. Comparison of assembly of normal and mutant recombinant proteins shows that fibronectin dimers are formed into multimeric complexes by binding to integrins at the cell surface which in turn stimulates fibril formation through binding to other fibronectin molecules. Mutant fibronectins that form structurally distinct fibril organizations have dramatic effects on cells such as delayed cytoskeletal reorganization and slowed cell cycle progression. Therefore, differences in fibronectin matrix can cause profound changes in intracellular functions and can modulate cell growth.
Fibronectin is also crucial in wound repair where it is first assembled along with fibrin into the blood clot provisional matrix that forms at sites of injury. We are using a synthetic fibronectin-fibrin clot matrix as a three-dimensional substrate for analyses of matrix control of cell behavior. Cells interacting with this matrix have a unique morphology with many lamellipodia indicating a motile phenotype. The provisional matrix in vivo contacts many other matrix proteins in the tissue around the wound. Incorporation of one of these proteins tenascin into the fibronectin-fibrin matrix induces a dramatic change to an elongated cell morphology with numerous actin-rich filopodia. Analyses of the signals induced by changes in the provisional matrix show that activation of the small GTPase RhoA is suppressed by tenascin. Thus, the cytoskeletal and cell shape changes result from differential regulation of members of the Rho GTPase family by distinct extracellular matrix components. This novel mechanism allows relatively modest changes in matrix composition to have major effects on cell responses.
Integrin receptors for extracellular matrix are highly conserved in all multicellular organisms and are the key to transmission of matrix information. We have generated transgenic nematodes that over-express a protein composed of the transmembrane and cytoplasmic domains of the Caenorhabditis elegans beta integrin subunit encoded by the pat-3 gene. These animals show dominant negative phenotypes consistent with disruption of endogenous integrin function such as defective muscle filament organization, movement defects, body deformities and infertility. Mutations in known binding sites within the beta(pat-3) cytoplasmic domain modulate the severity of these phenotypes. Transgenic nematodes with specific cytoplasmic domain mutations are now being developed for genetic screens to identify genes involved in intracellular signaling initiated via integrin engagement by extracellular matrix.
Minireview: Fibronectin in retinal disease. Exp Biol Med (Maywood). 2017 ;242(1):1-7. .
Collaboration of fibronectin matrix with other extracellular signals in morphogenesis and differentiation. Curr Opin Cell Biol. 2016 ;42:1-6. .
Stimulatory effects of advanced glycation endproducts (AGEs) on fibronectin matrix assembly. Matrix Biol. 2016 ;. .
Nerve Guidance by a Decellularized Fibroblast Extracellular Matrix. Matrix Biol. 2016 ;. .
Setting the bar for cell biology best practices. Mol Biol Cell. 2016 ;27(18):2803. .
Fibronectin matrix assembly is essential for cell condensation during chondrogenesis. J Cell Sci. 2014 ;127(Pt 20):4420-8. .
A cell-assembled, spatially aligned extracellular matrix to promote directed tissue development. J Mater Chem B Mater Biol Med. 2014 ;2(11):1449-1453. .
Effects of high glucose on integrin activity and fibronectin matrix assembly by mesangial cells. Mol Biol Cell. 2014 ;25(16):2342-50. .
Transcriptionally regulated cell adhesion network dictates distal tip cell directionality. Dev Dyn. 2014 ;243(8):999-1010. .
Reversible modulation of myofibroblast differentiation in adipose-derived mesenchymal stem cells. PLoS One. 2014 ;9(1):e86865. .
Jean E. Schwarzbauer, Ph.D., is the Eugene Higgins Professor of Molecular Biology at Princeton University. She is also a member of the New Jersey Center for Biomaterials, a core faculty member of the Center’s NIH Tissue Engineering training program, and an Associate member of the Rutgers Cancer Institute of New Jersey. Her research focuses on extracellular matrix assembly and cell-matrix interactions in normal and pathogenic situations including cartilage development, kidney fibrosis, tumor formation, and tissue repair and regeneration. She has published more than 125 papers and holds several patents related to her work. She received her B.S. in Chemistry from the University of Wisconsin – Milwaukee and studied protein-RNA interactions in the bacterial ribosome for her Ph.D. in Molecular Biology from the University of Wisconsin – Madison. After a post-doctoral fellowship at MIT studying the extracellular matrix protein fibronectin, she joined Princeton University as an Assistant Professor in 1986. Professor Schwarzbauer teaches cell biology at the undergraduate and graduate levels and, prior to becoming Associate Chair of the department, she served as the Director of Graduate Studies for the Molecular Biology Program from 2008 - 2013. In addition to her service to the department and the university, Professor Schwarzbauer also contributes to the scientific community with service on numerous boards and panels. She recently completed terms as President of the American Society for Matrix Biology, Secretary of the American Society for Cell Biology, and on the Gordon Research Conferences Board of Trustees. Currently, she is an editor for Molecular Biology of the Cell, associate editor for Matrix Biology, and on the editorial board of the Journal of Cell Biology. Her record of service also includes multiple NIH study sections (including chair of Pathobiochemistry and of Intercellular Interactions), review panels for the Wellcome Trust, ACS, DOD Breast Cancer Program, Deutsche Forschungsgemeinschaft, among others, and advisory boards for programs at U. Penn, Cornell University, NSF, and others. She has organized national and international conferences in matrix biology, cell biology, biomaterials, and bioengineering. She is the first recipient of the Peggy Wheelock Award for Excellence in Research, Mentoring, and Promotion of Women in Science at the Univ. of Nebraska Medical Center.
- President, American Society for Matrix Biology
- Keynote Speaker, 50th Anniversary of CMB Grad Program, UW-Madison