The myotendinous junction (MTJ) is the primary site for force transmission from the interior of the muscle cell, across its membrane, and to the extracellular matrix (ECM). In healthy muscle tissue, the MTJ provides resistance against the mechanical stress generated during muscle contraction, and it is now known that any decrease in MTJ stability leads to muscle detachment in diverse organisms. Most significantly, it is this detachment phenotype that typifies a series of congenital, progressive myopathies in humans. While many features concerning MTJ formation, structure, and function are conserved between both vertebrates and invertebrates, studies in the genetically tractable organism Drosophila melanogaster have proven instrumental in uncovering many proteins essential for MTJ assembly and function and muscle development as a whole. Therefore, the overall goal of this application is to use the fly model to better understand MTJ formation and how defects in MTJ stability may lead to the onset and progression of myopathies. The evolutionarily conserved Elmo-Myoblast city (Mbc) complex activates the small GTPase Rac during Drosophila muscle development. While the primary role of Rac lies in regulation of the actin cytoskeleton, other signaling components that function in Elmo-mediated myogensis - including the signals that initiate and regulate Elmo- Mbc activity - have remained elusive. This proposal expands upon preliminary data which show that (i) Elmo is also required for proper muscle-tendon attachment in the fly, and that (ii) there exist two new Elmo-binding proteins, both of which are required for muscle attachment at the MTJ. The role(s) of these Elmo-containing complexes will be examined using the mature Drosophila MTJ as a model for both muscle-tendon signaling and subsequent force transmission generated upon muscle contraction. To test our overall hypothesis that these new Elmo protein complexes function to mediate cytoskeletal rearrangement during Drosophila muscle attachment, we will use a powerful combination of genetic, biochemical, and imaging approaches to pursue the following specific aims: (1) dissect the role of Elmo in MTJ formation and/or Rac activation;(2) identify the mechanism by which Elmo and associated proteins function to maintain stable MTJs;and (3) understand the function of Elmo complexes in mitochondrial localization during muscle attachment.
Defects in the formation and/or function of stable muscle attachments are implicated in congenital human myopathies, and the progressive muscle weakness resulting from these myopathies is an obvious detriment to human health. The functional conservation of proteins required for muscle development across diverse species is well-established. Thus, we will use the well-established genetics in the fly to both define the roles of new proteins that contribute to muscle-tendon formation and function.
|Vishal, Kumar; Bawa, Simranjot; Brooks, David et al. (2018) Thin is required for cell death in the Drosophila abdominal muscles by targeting DIAP1. Cell Death Dis 9:740|
|Vishal, Kumar; Brooks, David S; Bawa, Simranjot et al. (2017) Adult Muscle Formation Requires Drosophila Moleskin for Proliferation of Wing Disc-Associated Muscle Precursors. Genetics 206:199-213|
|Brooks, David S; Vishal, Kumar; Kawakami, Jessica et al. (2016) Optimization of wrMTrck to monitor Drosophila larval locomotor activity. J Insect Physiol 93-94:11-17|
|Green, Nicole; Odell, Nadia; Zych, Molly et al. (2016) A Common Suite of Coagulation Proteins Function in Drosophila Muscle Attachment. Genetics 204:1075-1087|
|Wang, Zong-Heng; Clark, Cheryl; Geisbrecht, Erika R (2016) Analysis of mitochondrial structure and function in the Drosophila larval musculature. Mitochondrion 26:33-42|
|Wang, Zong-Heng; Clark, Cheryl; Geisbrecht, Erika R (2016) Drosophila clueless is involved in Parkin-dependent mitophagy by promoting VCP-mediated Marf degradation. Hum Mol Genet 25:1946-1964|
|Biersmith, Bridget; Wang, Zong-Heng; Geisbrecht, Erika R (2015) Fine-Tuning of the Actin Cytoskeleton and Cell Adhesion During Drosophila Development by the Unconventional Guanine Nucleotide Exchange Factors Myoblast City and Sponge. Genetics 200:551-67|
|Wang, Zong-Heng; Rabouille, Catherine; Geisbrecht, Erika R (2015) Loss of a Clueless-dGRASP complex results in ER stress and blocks Integrin exit from the perinuclear endoplasmic reticulum in Drosophila larval muscle. Biol Open 4:636-48|
|Liu, Ze Cindy; Odell, Nadia; Geisbrecht, Erika R (2013) Drosophila importin-7 functions upstream of the Elmo signaling module to mediate the formation and stability of muscle attachments. J Cell Sci 126:5210-23|
|Geisbrecht, Erika R; Sawant, Ketki; Su, Ying et al. (2013) Genetic interaction screens identify a role for hedgehog signaling in Drosophila border cell migration. Dev Dyn 242:414-31|
Showing the most recent 10 out of 12 publications