MARGARET T. FULLER


Professor
Department of Developmental Biology and Department of Genetics
Stanford University School of Medicine
Voice: 415/725-7681
Fax: 415/725-7739
E-mail:
fuller@cmgm.stanford.edu
1985 Searle Scholar


Research Interests

Regulation of Stem Cell Behavior
Cell Type Specific Transcription Machinery and Tissue Specific Gene Expression
Cell Cycle and Cell Morphogenesis During Male Gametogenesis
Mechanism of Cytokinesis


A central question in both developmental and cell biology concerns how the developmental program directs cellular differentiation. Once cell type and pattern decisions have been made, the developmental program remodels fundamental cellular functions like the cell cycle, the cytoskeleton, and the general transcription machinery to give rise to specialized cell types. We investigate the mechanisms that regulate and mediate cellular differentiation during male gametogenesis, using spermatogenesis in Drosophila a powerful genetic model system. Our current work focuses on three areas. 1) We are investigating the mechanisms that regulate the unique program of gene expression that takes place in primary spermatocytes in preparation for the dramatic morphogenetic events of spermatid differentiation. We have discovered that both progression of the meiotic cell cycle and expression of spermatid differentiation genes are regulated by tissue specific versions of the general PolII transcription machinery. In addition, our work implicates components upstream of the Rb pathway in the control of terminal differentiation. 2) We are exploring the mechanisms that regulate remodeling of sub-cellular organelles. Our studies revealed the first known protein mediator of mitochondrial fusion, required for formation of specialized mitochondrial structures in spermatids. Our current work indicates that human homologs of the Drosophila mitofusin protein regulate mitochondrial morphology in human cells and may play a role in apotosis as well. 3) We are dissecting the mechanisms that remodel the actin cytoskeleton and lead to localized assembly and constriction of the acto-myosin contractile machinery during cytokinesis. We have identified mutations in over 20 new genes that block different stages of contractile ring assembly and function during male meiosis. To investigate the underlying molecular mechanisms that regulate and mediate cytokinesis, we are cloning selected of these genes. Our initial results indicate that shared mechanisms involving addition of new membrane are required for both cleavage furrow constriction during cytokinesis and polarized cell elongation during later terminal differentiation.

A second focus of our work concerns the mechanisms that regulate stem cell behavior. Many highly differentiated but short-lived cell-types, including blood, skin, and sperm, are produced throughout adult life from stem cells. The central characteristic of stem cells is their remarkable, long-term capacity to divide as relatively undifferentiated precursors while also producing daugther cells that initiate differentiation. Understanding the mechanisms that regulate stem cell specification and the chioce between stem cell self-renewal and differentiation is crucial for realizing the potential of stem cells for regenerative medicine. We are using the Drosophila male germ line as a powerful genetic system to identify both the cell autonomous determinants and the extrinsic cell-cell interactions that govern stem cell behavior. Our results indicate that signals from surrounding somatic support cells specify asymmetric division of male germ line stem cells by inducing one daughter cell to self-renew stem cell identity while directing the other daughter cell to differentiate.

 

Publications:

Fuller, M.T. and J.King (1980) Regulation of coat protein polymerization by the scaffolding protein of Bacteriophage P22. Biophys. J. 32: 381-401.
Fish, S.R., K.A. Hartman, M.T. Fuller, J. King and G.J. Thomas (1980) Investigation of secondary structures and macromolecular interaction in
Bacteriophage P22 by laser Raman spectroscopy. Biophys. J. 32: 234-237.
King, J., R. Griffin-Shea and M.T. Fuller (1980) Scaffolding proteins and the genetic control of virus shell assembly. Quart. Rev. Biol. 55: 369-393.
Fuller, M.T and J. King (1981) Purification of the coat and scaffolding proteins from procapsids of bacteriophage P22. Virology 112: 529-547
Li, Y., G.J. Thomas, M.T. Fuller and J. King (1981) Investigations of Bacteriophage P22 by laser spectroscopy. In: Bacteriophage Assembly (M. DuBow, ed.), Alan R. Liss, Inc., New York, pp. 271-283.
Thomas, G.J., Y. Li, M.T. Fuller and J. King (1982) Structural studies of P22 phage, precursor particles, and proteins by laser Raman spectroscopy. Biochem. 16: 3866-3878.
Fuller, M.T. and J. King (1982) Assembly in vitro of Bacteriophage P22 procapsids from purified coat and scaffolding subunits. J. Mol. Biol. 156: 633-655.
Raff, E.C., and M.T. Fuller, T.C. Kaufman, K.J. Kemphues, J.E. Rudolph and R.A. Raff (1982) Regulation of tubulin gene expression during embryogenesis in Drosophila melanogaster. Cell 28: 33-40.
Raff, E.C. and M.T. Fuller (1984) Genetic analysis of microtubule function in Drosophila. In: Molecular Biology of the Cytoskeleton (Borisy, Cleveland and Murphy, eds.), Cold Spring Harbor Laboratory, New York, pp. 293-304.
Piperno, G. and M.T. Fuller (1985) Monoclonal antibodies specific for an acetylated form of a-tubulin recognize the antigen in cilia and flagella from a variety of organisms. J. Cell Biol. 101: 2085-2094.
Fuller, M.T. (1986) Genetic analysis of spermatogenesis in Drosophila: The role of the testis specific b tubulin and interacting genes in cellular morphogenesis. In: Gametogenesis and the Early Embryo, 44th Symposium of the Society for Developmental Biology (J. Gall, ed.), A.R. Liss, Inc., pp. 19-41.
Fuller, M.T., J.H. Caulton, J. Hutchens, T.C. Kaufman and E.C. Raff (1987) Genetic analysis of mictrotubule structure: A _-tubulin mutation causes the formation of aberrant microtubule in vivo and in vitro. J. Cell Biol. 104: 385-394.
Fuller, M.T., J.H. Caulton, J.A. Hutchens, T.C. Kaufman and E.C. Raff (1988) Mutations that encode partially functional b2-tubulin subunits have different effects on structurally different microtubule arrays. J. Cell Biol. 107: 141-152.
Wolf, N., C. Regan and M.T. Fuller (1988) Temporal and spatial pattern of differences in microtubule behavior during Drosophila embryogenesis revealed by distribution of a tubulin isoform. Development 102: 311-324.
Regan, C.L. and M.T. Fuller (1988) Interacting genes that affect microtubule function: The nc2 allele of the haywire locus fails to complement mutations in the testis-specific b-tubulin gene of Drosophila. Genes and Development 2: 82-92.
Hays, T., R. Deuring, B. Robertson, M. Prout and M.T. Fuller (1989) Interacting proteins identified by genetic interactions: A missense mutation in a-tubulin fails to complement alleles of the testis-specific _-tubulin of Drosophila. Mol. Cell. Biol. 9: 875-884.
Fuller, M.T., C. Regan, L. Green, B. Robertson, R. Deuring, and T. Hays (1989) Interacting genes identify interacting proteins involved in microtubule function in Drosophila. Cell Motility and the Cytoskeleton 14: 128-135.
Regan, C. and M.T. Fuller (1990) Interacting genes that affect microtubule function: Two kinds of mutations revert the failure to complement between haync2 and tubulin mutants. Genetics, 125: 77-90.
Green, L., N. Wolf, and M.T. Fuller (1990) Two types of genetic interaction implicate the whirligig gene of Drosophila melanogaster in microtubule organization in the flagellar axoneme. Genetics 126: 961-973.
Fuller, M. T., and P. G. Wilson (1992) Force and counter force in the mitotic spindle. Cell 71: 547-550.
Mounkes, L., R. Jones, B.-C. Liang, W. Gelbart, and M.T. Fuller (1992) A Drosophila model for Xeroderma pigmentosum and Cockayne's Syndrome: haywire encodes the fly homologue of ERCC3, a human excision repair gene. Cell 71: 925-937.
Fuller, M. T. (1993) Spermatogenesis. In The Development of Drosophila, (M. Martinez-Arias and M. Bate, eds.) Cold Spring Harbor Press, Cold Spring Harbor, New York. pp.71-147.
Hays, T. S., M. E. Porter, M. McGrail, P. Grissom, P. Gosch, M. T. Fuller, and J. R. McIntosh (1994) A cytoplasmic dynein motor in Drosophila: Identification and localization during embryogenesis. J. Cell Sci. 107: 1557-1569.
Fuller, M. T. (1995) Riding the polar winds: Chromosomes motor Down East. Cell 81: 5-8.
Lin, T.-Y., S. Viswanathan, C. Wood, N. Wolf, P. G. Wilson, and M. T. Fuller (1996) Coordinate developmental control of the meiotic cell cycle and spermatid differentiation in Drosophila males. Development 122: 1331-1341.
Hime. G. R., J. Brill, and M. T. Fuller (1996) Assembly of ring canals in the male germ line from structural components of the contractile ring. J. Cell Sci. 109: 2779-2788.
Wilson, P. G., M. T. Fuller, G. G. Borisy (1997) Monastral bipolar spindles: Implications for dynamic centrosome organization. J. Cell Sci. 110: 451-464.
Wilson, P. G., Y. Zheng, C. E. Oakley, B. R. Oakley, G. G. Borisy, and M. T. Fuller (1997) Differential expression and utilization of two gamma tubulin isoforms during gametogenesis in Drosophila. Devel. Biol. 184: 207-221.
Molina, I., S. Baars, J. A. Brill, K. G. Hales, M. T. Fuller, and P. Ripoll (1997) A chromatin associated kinesin-related protein required for normal mitotic chromosome segregation in Drosophila. J. Cell Biology 139: 1361-1371.
Hales, K. and M. T. Fuller (1997) Developmentally regulated mitochondrial fusion mediated by a conserved novel predicted transmembrane GTPase. Cell 90: 121-129.
White-Cooper, H., M. Schafer, L. S. Alphey, and M. T. Fuller (1998) Transcriptional and post-transcriptional control mechanisms coordinate the onset of spermatid differentiation with meiosis I in Drosophila. Development 125:125-134.
Fuller, M. T. and H. White-Cooper (1998) Genetic control of meiosis and the onset of spermiogenesis in Drosophila. In Testicular Function: from Gene Expression to Genetic Manipulation (M. Stefanini, C. Boitani, M. Galdieri, R. Geremia, and F. Palombi, eds.) Springer-Verlag, Heidelberg. pp.59-81.
Mounkes, L. and M. T. Fuller (1998) The DUG gene of Drosophila melanogaster encodes a structural and functional homologue of the S. cerevisiae SUG1 predicted ATPase associated with the 26S proteasome. Gene 206: 165-174.
Hermann, G. J., J. Thatcher, K. G. Hales, J. P. Mills, M. T. Fuller, J. Nunnari, and J. M. Shaw (1998) Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p. J. Cell Biology 143: 359-374.
Fuller, M. T. (1998) Genetic control of cell proliferation and differentiation in Drosophila spermatogenesis. In The Male Germ Cell: Migration to Fertilization (A.R. Bellve, ed.) Seminars in Cell and Developmental Biology 9: 433-444.
Mounkes, L. and M. T. Fuller (1999) Molecular characterization of mutant alleles of the DNA repair/basal transcription factor haywire/ERCC3 in Drosophila. Genetics 152: 291-297.
Kiger, A. A., S. Gigliotti, and M. T. Fuller (1999) Developmental genetics of the essential Drosophila nucleoporin nup154: Allelic differences due to an outward directed promoter in the P element 3' end. Genetics 153: 799-812.
Lin, T.-Y., M. J. Pringle, and M. T. Fuller (2000) Regulation of meiosis and spermatid differentiation in Drosophila primary spermatocytes. In The Testis: from Stem Cell to Sperm Function (E. Goldberg, ed.) Springer Verlag, N.Y. pp. 120-132.
Brill, J., G. R. Hime, M. Scharer-Schuksz, and M.T. Fuller (2000) A phospholipid kinase regulates actin disassembly and intercellular bridge formation during germ line cytokinesis. Development 127: 3855-3864.
Kiger, A., H. White-Cooper, and M. T. Fuller (2000) Somatic support cells restrict germ line stem cell self-renewal and promote differentiation. Nature 407: 750-754.
White-Cooper, H., Leroy, D., MacQueen, A. and Fuller, M. T. (2000) Transcription of meiotic cell cycle and terminal differentiation genes depends on a conserved chromatin associated protein, whose nuclear localization is regulated. Development 127: 5463-5473.
Santel, A. and M. T. Fuller (2001) Control of mitochondrial morphology by a human Mitofusin protein. J. Cell Sci. 114: 867-874..
Kiger, A. and Fuller, M. T. (2001) Male Germ Line Stem Cells. In Stem Cell Biology, (D. Gottlieb, R. Gardner, and D. Marshak, eds.) Cold Spring Harbor Press, Cold Spring Harbor, New York. pp.149-187.
Hiller, M., T.-Y. Lin, C. Wood, and M. T. Fuller (2001) Developmental control of transcription by a tissue specific TAF homolog. Genes and Development 15: 1021-1030.
Kiger, A.A., D.L. Jones, C. Schulz, M. Rogers, and M. T. Fuller (2001) Signaling from a support cell niche specifies stem cell self-renewal via JAK-STAT activation. Science 294: 2542-2545.
Schulz, C., L. Perezgasga, and M. T. Fuller: Expression and functional analysis of a Drosophila Aminopeptidase. Dev. Genes Evol. 211: 581-588.
Tazuke, S.I., C. Schulz, L. Gilboa, M. Fogarty, A. Mahowald, A. Guiche, A. Ephrussi, C.G. Wood, R. Lehmann, and M. Fuller. (2002). A germ line specific gap junction protein required for survival of differentiating early germ cells. Development 129: 2529-2539.

Hwa, J.J., M.A. Hiller, M.T. Fuller and A. Santel. (2002) Differential expression of the Drosophila mitofusin genes fuzzy onions (fzo) and dmfn. Mechanisms of Development 116: 213-216.

Schulz, C., C. Wood, D. L. Jones, S. Tazuke, and M. T. Fuller: Signaling from germ cells mediated by the rhomboid homolog stet organizes encapsulation by somatic support cells. Development 129: 4523-4523
Farkas, R. M., M. G. Giansanti, M. Gatti, M.T. Fuller. (2002). The Drosophila Cog5 homolog is required for cytokinesis, polarized cell growth, and assembly of specialized Golgi architecture during spermatogenesis. Molecular Biology of the Cell. in press.

Patent
Hales, K. and M. T. Fuller "Mitofusin genes and their uses". Application Number # 09/09808 filed 6/4/98. CIP filed 10/99 added Ansgar Santel. Curriculum Vitae

Education and Employment:
A.B.: Physics (June 1974). Brandeis University
Ph.D.: Microbiology (January 1980). Massachusetts Institute of Technology
Jane Coffin Childs Postdoctoral Fellow, Indiana University (1980-1983).
Assistant Professor (1983-1989) and Associate Professor (1989-1990), Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder
Associate Professor (1990-2000), Department of Developmental Biology and Department of Genetics, Stanford University School of Medicine
Professor (2000-present), Department of Developmental Biology and Department of Genetics, Stanford University School of Medicine

Awards and Honors
Phi Beta Kappa, 1973
Summa Cum Laude with Honors (from Brandeis University), 1974
Dr. Joseph Garrison Parker Prize for excellence in the Arts and Sciences, 1974
NIH Predoctoral NRSA Fellowship, 1976-79
Jane Coffin Childs Memorial Fund for Medical Research Postdoctoral Fellow, 1980-83
American Cancer Society Junior Faculty Research Award, 1983-86
Searle Scholars Award, 1985-88
American Cancer Society Scholar in Cancer Research Award, 1994-95
Mary Ingraham Bunting Fellow, Radcliffe College, 1994-95Professional Service
NIH "Cell and Molecular' Study section, 1988
NIH Genetics Study Section, 1989
Co-organizer Boulder Winter Symposium "Developmental and Molecular Genetics of Pattern Formation in Drosophila" 1988
Chair of Minisymposium on "Molecular Genetics of the Cytoskeleton", ASCB meeting, 1989
Co-organizer of National Drosophila Research Conference 1990.
Organized Workshop on Spermatogenesis at National Drosophila Research Conference 1994.
Associate Editor, Genetics, 1989-1994
Editorial Board, Molecular Biology of the Cell, 1994-present
Chair, Sandler Lecture Selection Committee, National Drosophila Meeting 1995
EMBO International Drosophila Meeting, Scientific Organizing Committee 1996
Co-Chair of Minisymposium on "Perpetuation of the Species: Gametogenesis and Fertilization", ASCB National meeting, 1999
Organizer UCLA/Keystone Meeting "Stem Cells, Asymmetric Cell Divisions, and Cell Fate" 2000
Co-Organizer of FASEB meeting on Transcription Regulation during Cell Growth, Differentiation and Development, 2001.
Searle Scholars Advisory Board

Professional Service

NIH "Cell and Molecular" Study section, 1988

NIH Genetics Study Section, 1989

Co-organizer Boulder Winter SYmposium "Developmental and Molecular Genetics of pattern Formation in Drosophila" 1988

Chair of Minisymposium on "Molecular Genetics of the Cytoskeleton", ASCB meeting, 1989.

Co-organizer of National Drosophila Research Conference, 1990.

Orgaanized Workshop on Spermatogenesis at National Drosophila Research Conference, 1994.

Associate Editor, Genetics, 1989-1994.

Editorial Board, Molecular Biology of the Cell, 1994-present.

Chair, Sandler Lecture Selection Committee, National Drosophila Meeting, 1995.

EMBO, International Drosophila Meeting, Scientific Organizing Committee, 1996.

Co-Chair of Minisymposium on "Perpetuation of the Species: Gametogenesis and Fertilization", ASCB National meeting, 1999.

Organizer UCLA/Keystone Meeting "Stem Cells, Asymmetirc Cell Divisions, and Cell Fate", 2000.

Co-Organizer of FASEB meeting on "Transcription Regulation during Cell Growth, Differentiation and Development", 2001.

Searle Scholars Advisory Board.