Susan Abmayr - Stowers Institute for Medical Research

Research Focus

     Research in my lab focuses on the mechanisms by which determined cells implement cell fate decisions and differentiate into mature tissues. We have chosen to use the embryonic development of the larval body wall muscles as a model system. The body wall muscles of a Drosophila larva include a unique array of multinucleate muscle fibers that are generated by fusion between two distinct populations of myoblasts. The first, termed founder myoblasts, are located in characteristic and reproducible positions in the embryo and contain information that specifies muscle identity, size, position, and attachment. As such, they dictate the muscle pattern and seed the fusion process. The second more populous group of myoblasts has been termed the fusion-competent myoblasts (FCMs). As defined, these cells are committed to myogenesis, but have no inherent fiber specificity. Rather, observations in both Drosophila and the grasshopper have demonstrated that each muscle fiber is generated by the fusion of a single founder cell with several mesodermally derived fusion-competent cells.

     Recognition, migration and adhesion between the founder cells and FCMs is a critical prerequisite to myoblast fusion, and is controlled by members of the immunoglobulin superfamily. The SNS protein is specifically expressed on the surface of the FCMs and is absent from the founder myoblasts. SNS is essential for FCMs to associate with founder myoblasts and mutations in SNS are characterized by the inability of the myoblasts to associate and the absence of multinucleate muscle fibers. SNS, in turn, associates with IgSF members such as Duf/Kirre and IrreC/Rst that are expressed in the founder myoblasts. Indeed, SNS and Duf/Kirre or IrreC/Rst are sufficient to direct association of nonmuscle cells in culture. Moreover differential affinity of these molecules for each other is sufficient to account for the observation that founder cells do not interact with other founder cells and FCMs do not interact with other FCMs. As a transmembrane protein in which the cytodomain plays a critical role, SNS also functions in signal transduction from sites of contact between myoblasts to events in the cell that appear to be critical for their fusion into muscle syncitia. Thus, SNS provides us with the opportunity to examine the biochemical requirements for this interaction, to identify critical interacting proteins, and to identify components downstream of SNS in this signaling pathway. SNS is also a valuable marker for examining the behavior of the FCMs, and efforts are underway to generate reporters using FCM-specific enhancer regions. These reporters allow us to follow the development and behavior of the FCMs, and to visualize their migration and fusion in living embryos. Additionally, identification of SNS enhancers that drive its expression in other tissues has revealed roles for SNS in other locations within the embryo. These cell types are under investigation to determine whether SNS as well as other components of the SNS pathway impact their development and/or morphological behavior.

     Our efforts are also directed toward understanding the role of more ubiquitously expressed proteins that are critical for myoblast fusion. Among these is the Drosophila myoblast city (mbc) locus. MBC was a founding member of the CDM superfamily which, along with MBC, includes C. elegans CED-5, human Dock180, and almost 20 additional members in a wide variety of species. These proteins function as non-conventional guanine nucleotide exchange factors for small GTPases such as rac1, in a pathway that regulates organization of the actin cytoskeleton. In many instances, these CDM proteins function in a complex with the SH2—SH3 adaptor protein Crk and with the PH domain containing protein CED-12/ELMO. Current efforts are directed toward the identification of other components of this signaling pathway in Drosophila, and elucidation of their role in myoblast fusion, their genetic and biochemical interactions, and their upstream regulators. Components of the conserved CDM signaling cascade impact other cell types and behaviors that include oncogenic transformation, phagocytosis, and cell migration. Ongoing studies in the lab are also directed toward these pathways in Drosophila in an effort to determine which components are involved and to identify additional pathway components.

Academic Appointment: Associate Professor, Department of Anatomy & Cell Biology, The University of Kansas School of Medicine

Selected publications

Kocherlakota KS, Wu JM, McDermott J, Abmayr SM. Analysis of the Cell Adhesion Molecule Sticks-and-Stones Reveals Multiple Redundant Functional Domains, Protein-Interaction Motifs and Phosphorylated Tyrosines that direct Myoblast Fusion in Drosophila melanogaster. Genetics. 2008. Abstract

Geisbrecht ER, Haralalka S, Swanson SK, Florens L, Washburn MP, Abmayr SM. Drosophila ELMO/CED-12 interacts with Myoblast city to direct myoblast fusion and ommatidial organization. Dev Biol. 2008;314:137-149. Abstract

Balagopalan L, Chen MH, Geisbrecht ER, Abmayr SM. The CDM superfamily protein MBC directs myoblast fusion through a mechanism that requires phosphatidylinositol 3,4,5-triphosphate binding but is independent of direct interaction with DCrk. Mol Cell Biol. 2006;26:9442-9455. Abstract

Guelman S, Suganuma T, Florens L, Weake V, Swanson SK, Washburn MP, Abmayr SM, Workman JL. The Essential Gene wda Encodes a WD40 Repeat Subunit of Drosophila SAGA Required for Histone H3 Acetylation. Mol Cell Biol. 2006;26:7178-7189. Abstract

Guelman S, Suganuma T, Florens L, Swanson SK, Kiesecker CL, Kusch T, Anderson S, Yates JR, 3rd, Washburn MP, Abmayr SM, Workman JL. Host cell factor and an uncharacterized SANT domain protein are stable components of ATAC, a novel dAda2A/dGcn5-containing histone acetyltransferase complex in Drosophila. Mol Cell Biol. 2006;26:871-882. Abstract

Abmayr SM, Kocherlakota KS. Muscle morphogenesis: the process of embryonic myoblast fusion. In: H Sink, ed. Muscle Development in Drosophila. Georgetown, Tex. New York, N.Y.: Landes Bioscience/Eurekah.com ;Springer Science+Business Media; 2006:p.1-12. Table of Contents

Abmayr SM, Balagopalan L, Galletta BJ, Hong S-J. Myogenesis and Muscle Development. In: L Gilbert, I K., and S Gill, eds. Comprehensive Molecular Insect Science. 1st ed. San Diego, CA: Pergamon; Elsevier LTD; ^©2005;2:p. 1-45. Table of Contents

Kusch T, Florens L, Macdonald WH, Swanson SK, Glaser RL, Yates III JR, Abmayr SM, Washburn MP, Workman JL. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science. 2004;306:2084-2087. Abstract

Galletta BJ, Chakravarti M, Banerjee R, Abmayr SM. SNS: adhesive properties, localization requirements and ectodomain dependence in S2 cells and embryonic myoblasts. Mech Dev. 2004;121:1455-1468. Abstract

Workman JL, Abmayr SM. Histone H3 variants and modifications on transcribed genes. Proc Natl Acad Sci U S A. 2004;101:1429-1430. Abstract

Abmayr SM, Workman JL. Transcription factors prominently in Lasker Award to Roeder. Cell. 2003;115:243-246. Abstract

Presgraves DC, Balagopalan L, Abmayr SM, Orr HA. Adaptive evolution drives divergence of a hybrid inviability gene between two species of Drosophila. Nature. 2003;423:715-719. Abstract.

Kusch T, Guelman S, Abmayr SM, Workman JL. Two Drosophila Ada2 homologues function in different multiprotein complexes. Mol Cell Biol. 2003;23:3305-3319. Abstract.

Abmayr SM, Balagopalan, L, Galletta BJ, Hong, S-J. Cell and molecular biology of myoblast fusion. Int'l Rev Cyt. 2003;225: 33-89. Abstract.

Balagopalan L, Keller CA, Abmayr SM. Loss-of-function mutations reveal that the Drosophila nautilus gene is not essential for embryonic myogenesis or viability. Dev Biol. 2001;231:374-382. Abstract.

Bour BA, Chakravarti M, West J, Abmayr SM. Drosophila SNS, a member of the immunoglobulin superfamily that is essential for myoblast fusion. Genes Dev. 2000;14:1498-1511. Abstract.

Galletta BJ, Niu X-P, Erickson MRS, and Abmayr SM. Identification of a Drosophila homologue to Crk by interaction with MBC. Gene. 1999;228:243-252. Abstract.

Keller, CA, Grill MA and Abmayr SM. A role for nautilus in the differentiation of muscle precursors. Dev Biol. 1998;202:157-171. Abstract.

Abmayr SM, Keller CA. Drosophila myogenesis, and insights into the role of nautilus. Curr Topics Dev Biol. 1998;38:35-80. Abstract.

Erickson MRS, Galletta BJ, Abmayr SM. Drosophila mbc encodes a conserved protein that is essential for myoblast fusion, dorsal closure and cytoskeletal organization. J Cell Biol. 1997;138:589-603. Abstract.

Lin M-H, Bour BA, Abmayr SM, Storti RV. Ectopic expression of MEF2 in the epidermis induces epidermal expression of muscle genes and abnormal muscle development in Drosophila. Dev Biol. 1997;182:240-255. Abstract.

Keller CA, Erickson MS, Abmayr SM. Misexpression of nautilus induces myogenesis in cardioblasts and alters the pattern of somatic muscle fibers. Dev Biol. 1997;181:197-212. Abstract.

Rushton E, Drysdale R, Abmayr SM, Michelson AM, Bate M. Mutations in a novel gene, myoblast city, provide evidence in support of the founder cell hypothesis for Drosophila muscle development. Development. 1995;121:1979-1988. Abstract.

Bour BA, O'Brien MA, Lockwood WL, Goldstein ES, Bodmer R, Taghert PH, Abmayr SM, Nguyen HT. Drosophila MEF2, a transcription factor that is essential for myogenesis. Genes Dev. 1995;9:730-741. Abstract.

Abmayr SM, Erickson MS, Bour BA. Embryonic development of the larval body wall musculature of Drosophila. Trends Genet. 1995;11:153-159. Abstract.

Nguyen HT, Bodmer R, Abmayr SM, McDermott JC, Spoerel NA. D-mef2: A Drosophila mesoderm-specific MADS box-containing gene with a biphasic expression profile during embryogenesis. Proc Natl Acad Sci USA. 1994;91:7520-7524. Abstract.

Abmayr SM, Workman JL. Preparation of nuclear extracts from cultured cells. In: Ausubel FM, Brent R, Kingston RE, Moore DD, Siedman JG, Smith JA, Struhl K, eds. Short Protocols in Molecular Biology. New York, NY: Greene Publishing Associates/Wiley Interscience; 1992:12.3-12.5.

Abmayr SM, Michelson AM, Corbin V, Young MW, Maniatis T. nautilus, a Drosophila member of the myogenic regulatory gene family. In: Blau H, Kelly A, eds. Gene Expression and Neuromuscular Development. New York, NY: Raven Press;1992. Keystone Symposium Proceedings Series. 1-16.

Corbin V, Michelson AM, Abmayr SM, Neel V, Alcamo E , Maniatis T, Young MW. A role for the Drosophila neurogenic genes in mesoderm differentiation. Cell. 1991;67:311-323. Abstract.

Michelson AM, Abmayr SM, Bate CM, Martinez Arias M, Maniatis T. Expression of a MyoD family member prefigures muscle pattern in Drosophila embryos. Genes Dev. 1991;4:2086-2097. Abstract.