Faculty, Graduate Program
Actin Cytoskeleton in Cell and Tissue Architecture, Physiology and Pathology
Our research aims to unravel how temporal and spatial control of actin dynamics creates the diverse cytoskeletal structures that determine cell and tissue architecture, physiology and pathology. Since the discovery of tropomodulins (Tmods), as a family of actin filament (F-actin) pointed end capping proteins by our lab, we continue to study Tmods and related family members, leiomodins (Lmods), together with their F-actin binding partners and co-regulators. These include tropomyosins (TMs), which bind along actin filaments and protect them from disassembly and mechanical breakage; and non-muscle myosins (NMIIs), which pull on TM-coated F-actin to exert contractile forces. We currently study three cell types: red blood cells (RBCs), megakaryocytes (MKs), and the ocular lens. In these cells, we study the diverse and cooperative functions of Tmods, TMs, and NMIIs that affect F-actin on cell membranes, providing stability and exerting contractile forces to shape membrane curvature and influence cell and tissue biomechanical properties. We strive to perfect classical methods and develop novel protocols to study cell and tissue properties. Our wide ranging approaches include biochemistry and biophysics, conventional and super-resolution fluorescence microscopy, live cell imaging, mouse genetics and physiology, and analysis of human cells from patients with congenital diseases, allowing us to study physiology, aging and pathology from the macro to the micro scale.
Overarching questions are:
(1) What are the common and diverse molecular mechanisms that specify actin filament architecture and function in cells and tissues?
(2) What insights can mutations and genetic perturbations provide into normal tissue development and physiology, and what are the pathological mechanisms of actin dysregulation in human aging and disease?When answering these questions, our multidisciplinary and multi-scale approach allows us to connect the dots -- from actin dynamics regulation, to organization of cytoskeletal structures in cells, to morphogenetic differentiation during development, to cell and tissue physiology in health and disease.
B.A., Oberlin College, 1974
Ph.D., Harvard University, 1980
1980-1982 Jane Coffin Childs Postdoctoral Fellow NIADDK, NIH, and Dept Cell Biology and Anatomy, Johns Hopkins University School of Medicine; 1983-1984 Research Associate, Dept Cell Biology and Anatomy, Johns Hopkins University School of Medicine; 1984-1987 Assistant Professor, Dept Anatomy and Cell Biology, Harvard Medical School; 1987-1993 Assistant Professor, Depts Molecular and Cell Biology, The Scripps Research Institute (TSRI); 1993-2000 Associate Professor, Dept Cell Biology, TSRI; 2000-2013 Professor, Dept Cell Biology, TSRI; 2013 Professor, Dept Cell and Molecular Biology, TSRI; 2013- Associate Dean for Graduate Studies, TSRI; 2014-2015 Chair (Acting), Department of Cell and Molecular Biology,TSRI; 2017-pres. Professor, Department of Molecular Medicine, TSRI.
1975-1978 National Science Foundation Predoctoral Fellowship Award; 1980-1982 Jane Coffin Childs Foundation Postdoctoral Fellowship Award; 1983-1984 NIH New Investigator Research Grant Award; 1990-1995 American Heart Association Established Investigator Award; 2001-2003 Chair, Cell and Developmental Function 6 (CDF6) Study Section for Postdoctoral Fellowships and AREA grants, NIH; 2003 Chair, “Motile and Contractile Systems” Gordon Research Conference, Colby-Sawyer College, NH; 2009-2010 Erythrocyte and Leukocyte Biology (ELB) NIH Study Section; 2010-2013 Molecular and Cellular Hematology (MCH) NIH Study Section; 2010 ASCB Program Committee, 2011 Annual Meeting; 2011 Chair, “Red Cells” Gordon Research Conference, Proctor Academy, Andover, NH; 2011 Lens and Cataract Program Planning Panel, National Eye Institute, NIH; 2011-pres. Associate Program Director & Imaging Core Director, San Diego Skeletal Muscle Research Center (NIAMS/NIH), P30 Core for UCSD, TSRI, Sanford-Burnham, Salk and San Diego State University; 2014 Program Organizer Lens Section, International Society for Eye Research XX1st Biennial Conference. Editorial Boards and Consulting: 2005- Editorial Board, Cytoskeleton; 2012-2013, Editorial Board Member, Journal of Biological Chemistry; 2013-pres. Associate Editor, Journal of Biological Chemistry, 2017- Chair, ARVO Annual Meeting Program Committee, Lens Section (LE).
For a complete list of publications: http://www.scripps.edu/fowler/publications.html
Cheng C, Nowak RB, Fowler VM. The lens actin filament cytoskeleton: diverse structures for complex functions. Exp. Eye Res. 2016. S0014-4835(16)30035-5.
Gokhin DS, Fowler VM. Software-based measurement of thin filament lengths: an open-source GUI for Distributed Deconvolution analysis of fluorescence images. J. of Microscopy. 2016. 265 (1) 11-20
Cheng C., Nowak, RB, Biswas SK, Lo WK, FitzGerald PG, Fowler VM. Tropomodulin 1 regulation of actin is required for the formation of large paddle protrusions between mature lens fiber cells. Invest. Ophthalmol. Vis. Sci.; 2016. Vol.57, 4084-4099.
Cheng C, Gokhin DS, Nowak RB, Fowler VM. Sequential application of glass coverslips to assess the compressive stiffness of the mouse lens. J. of Visualized Experiments, 2016. 3;(111).
Gokhin DS, Ochala J, Domenighetti AA, Fowler VM. Tropomodulin1 directly controls thin filament length in both wild-type and tropomodulin4-deficient skeletal muscle. Development, 2015. 142(24):4351-62.
Sui Z, Nowak RB, Sanada C, Halene S, Krause DS, Fowler VM. Regulation of actin polymerization by tropomodulin3 controls megakaryocyte actin organization and platelet biogenesis. Blood. 2015. 126(4):520-530.
Cheng C., Nowak RB, Gao J, Sun X, Biswas SK, Lo W-K, Mathias RT, Fowler VM. Lens ion homeostasis relies on the assembly of large connexin 46 gap junction plaques on the broad sides of differentiating fiber cells. Amer. J. Physiol. Cell Physiol. 2015. 308: C835-C847.
Gokhin DS, Nowak RB, Khoory JA, de la Piedra A, Ghiran IC, Fowler VM. Dynamic actin filaments control the mechanical behavior of the human red blood cell membrane. Mol. Biol. Cell. 2015. 26(9):1699-710.
Yuen M, Sandaradura SA, Dowling JJ, et al. Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy. J. Clin. Invest. 2015. 125(11):456-7.
Yamashiro S., Gokhin DS, Sui Z, Bergeron SE, Rubenstein PA, Fowler VM. Differential regulatory activities of tropomodulin1 and tropomodulin3 with diverse tropomyosin and actin isoforms. J. Biol. Chem. 2014. 289(17):11616-29.
Ochala J., Gokhin DS, Iwamoto H, Fowler VM. Pointed end capping by tropomodulin modulates actomyosin crossbridge formation in skeletal muscle fibers. FASEB J. 2014. 28:408-415
Sui Z., Nowak RB, Bacconi A, Kim NE, Liu H, Li J, Wickrema A, An XL, Fowler VM. Tropomodulin3-null mice are embryonic lethal with anemia due to impaired erythroid terminal differentiation in the fetal liver. Blood. 2014. 123:758-767, With accompanying cover image.
Fowler VM. The human erythrocyte plasma membrane: a rosetta stone for decoding membrane–cytoskeleton structure. Curr. Top. Membr. 2013. 72:39-88.
Gokhin DS, Nowak RB, Kim NE, Arnett EE, Chen AC, Sah RL, Clark JI, Fowler VM. Tmod1 and CP49 synergize to control the fiber cell geometry, transparency, and mechanical stiffness of the mouse lens. PLoS ONE. 2012. 7(11): e48734
Yamashiro S, Gokhin DS, Kimura S, Nowak RB, Fowler VM. Tropomodulins: Pointed-end capping proteins that regulate actin filament architecture in diverse cell types. Cytoskeleton (Hoboken). 2012. 69(6):337-70.
Gokhin DS, Kim NE, Lewis SA, Hoenecke HR, D'Lima DD, Fowler VM. Thin-filament length correlates with fiber type in human skeletal muscle. Am. J. Physiol. Cell Physiol. 2012. 302(3):C555-65
Damani S, Bacconi A, Libiger O, Chourasia AH, Serry R, Gollapudi R, Goldberg R. Rapeport K, Haaser S,K, Kuhn P, Wood M, Carragher B, Schork NJ, Jiang J, Rao C, Connelly M, Fowler VM, Topol EJ. Characterization of Circulating Endothelial Cells in Acute Myocardial Infarction. Science Translational Medicine. 2012. 4(126):126ra33.
Gokhin DS, Fowler VM. Cytoplasmic γ-actin and tropomodulin isoforms link to the sarcoplasmic reticulum in skeletal muscle fibers. J Cell Biol. 2011 July 11; 194(1):105-20.
Fath T, Fischer RS, Dehmelt L, Halpain S, Fowler VM. Tropomodulins are negative regulators of neurite outgrowth. Eur J Cell Biol. 2011. Apr; 90(4):291-300.
Moyer JM, Nowak RB, Kim NE, Larkin SK, Peters LL, Hartwig J, Kuypers FA, Fowler VM. Tropomodulin1 null mice have a mild spherocytic elliptocytosis with appearance of tropomodulin3 in red blood cells and disruption of the membrane skeleton. Blood. 2010. 116:2590-2599.