Programmed Cell Death
Programmed cell death is a fundamental component of development and homeostasis in virtually all organisms. Defects in the regulation of cell death serves as the basis of many human diseases, including auto-immunity, neurodegeneration and most cancers.
To define the molecular mechanisms that mediate this process, we have exploited the intersegmental muscles (ISM) of moth as a model system. These giant cells are used to propel the moth out of the pupal cuticle at the end of metamorphosis, and then they die during a 36 hour period in response to a specific hormonal trigger. The ability of the ISMs to commit suicide requires de novo gene expression, and we have use a variety of molecular techniques to clone death-associated transcripts from these cells. As part of our on-going analysis of these novel genes, we have also cloned their mammalian homologs to determine their roles in myogenesis and disease.
Following declines in available trophic support, myoblasts make one of several key decisions. Some cells activate both survival and differentiation programs and fuse to form multinucleated myotubes. Others activate survival programs and arrest as mitotically-competent mononucleated satellite cells. The remainders die by apoptosis. The genes we initially isolated from the ISMs appear to play key roles in this decision making process. For example, Acheron acts early in myogenesis to determine if myoblasts should remain as lineage-restricted stem cells or instead differentiate or die. Thus, not only does this work enhance our understanding of myogenesis as a developmental process, but it may also provide powerful tools for regulating the survival of myoblasts that are used for regenerative medicine and gene therapy.
Schwartz, L.M. and Truman, J.W. 1982. Peptide and Steroid Regulation of Muscle Degeneration in an Insect. Science, 215: 1420-1421.
Schwartz, L.M. and Truman, J.W. 1984. Cyclic GMP May Serve as a Second Messenger in Peptide-Induced Muscle Degeneration in an Insect. Proc. Natl. Acad. Sci. USA, 81: 6718-6722.
Schwartz, L.M. and Stühmer, W. 1984. Voltage-Dependent Sodium Channels in an Invertebrate Striated Muscle. Science, 225: 523-525.
Schwartz, L.M., McClesky, E.W. and Almers, W. 1985. Dihydropyridine Receptors in Muscle are Voltage-Dependent, But Most Are Not Functional Calcium Channels. Nature, 314: 747-751.
Schwartz, L.M., Kosz, L., and Kay, B.K. 1990. Gene Activation is Required for Developmentally Programmed Cell Death. Proc. Natl. Acad. Sci. USA, 87: 6594-6598.
Schwartz, L.M., Myer, A., Kosz, L., Engelstein, M., and Maier, C. 1990. Activation of Polyubiquitin Gene Expression during Developmentally Programmed Cell Death. Neuron, 5: 411-419.
Schwartz, L.M., Smith, S., Jones, M.E.E., and Osborne B.A. 1993. Do All Programmed Cell Deaths Occur Via Apoptosis? Proc. Natl. Acad. Sci. USA, 90: 980-984.
Liu, Z-G., Smith, S., McLaughlin, K.A., Schwartz, L.M. and Osborne B.A. 1994. Apoptotic Signals Delivered Through the T Cell Receptor Require the Immediate Early Gene Nur77. Nature, 367: 281-284.
Milligan, C.E., Prevette, D., Yaginuma, H., Homma, S., Cardwell, C., Fritz, L.C., Tomeselli, K.J., Oppenheim, R.W. and Schwartz, L.M. 1995. Peptide inhibitors of the ICE protease family arrest programmed cell death of motoneurons in vitro and in vivo. Neuron, 15: 385-393.
Schwartz, L.M. and Osborne, B.A. 1995. Editors Methods in Cell Biology Series, CELL DEATH. Academic Press, pp459.
Zhou, L., Schnitzler, A., Agapite, J., Schwartz, L.M., Steller, H., and Nambu, J.R. 1997. Cooperative functions of the reaper and head involution defective genes in the programmed cell death of Drosophila CNS midline cells. Proc. Natl. Acad. Sci. USA, 94: 5131-5136.
Hu, Y., Cascone, P., Cheng, L., Sun, D., Nambu, J.R., and Schwartz, L.M. 1999. Lepidopteran DALP, And Its Mammalian Ortholog Hic-5, Function as Negative Regulators of Muscle Differentiation. Proc. Natl. Acad. Sci. USA, 96: 10218-10223.
Schwartz, L.M. and Ashwell, J. 2001. Editors Methods in Cell Biology Series, Apoptosis. Academic Press, volume 66, pp533.
Wing, J.P., Karres, J., Ogdahl, J.A., Zhou, L., Schwartz, L.M. and Nambu, J.R. 2002. Drosophila sickle is a novel grim-reaper cell death activator. Current Biology, 12: 131–135.
Schwartz, L.M., Nambu, J.N. and Wang, Z. 2002. Parkinsonism, Proteolysis, Proteasomes. Cell Death and Differentiation, 9: 479-482.
Schwartz, L.M. and Ruff, R.L. 2002. Changes in the contractile properties of skeletal muscle during developmentally programmed atrophy and death. American Journal of Physiology, 282: C1270-7.
Wing J.P., Schreader, B.A., Wang, Y., Andrews, P.A., Husseinovic, N., Dong, C.K. Ogdahl, J., Schwartz, L.M., White, K., Nambu, J.R. 2002. Drosophila Morgue is a novel F box/ubiquitin conjugase domain protein important in grim-reaper mediated programmed cell death. Nature Cell Biology, 4: 451-456.
Valavanis, C., Wang, Z., Sun, D. Vaine, M., and Schwartz, L.M. 2007. Acheron, a novel member of the Lupus Antigen family, is induced during the programmed cell death of skeletal muscles in the moth Manduca Sexta. Gene, 393: 101–109.
Bouchentouf, M., Benabdallah, B.F., Rousseau, J., Schwartz, L.M. and Tremblay, J.P. 2007. Induction of Anoikis following myoblast transplantation into SCID mouse muscles requires the Bit1 and FADD pathways. American Journal of Transplantation, 7: 1491–1505.
Gao, Z., Deblis, R., Glenn, H., and Schwartz, L.M. 2007. Differential Role Of Hic-5 Isoforms On The Regulation Of Cell Death And Myotube Formation During Myogenesis. Experimental Cell Research, 313: 4000-14.
Schwartz, L.M. 2008. Atrophy and programmed cell death of skeletal muscle. Cell Death and Differentiation. 15:1163-9.
Weng, H., Kim, C., Valavanis, C., Wang, Z., and Schwartz, L.M. 2009. Acheron, a Novel La Antigen Family Member, Binds To CASK And Forms A Complex With Id Transcription Factors. Cellular and Molecular Biology Letters, 14:273-287.
Myer, A., Mason, H.A., Smith, W., Brown, C. and Schwartz, L.M. 2009. Differential Control Of Cell Death And Gene Expression During Two Distinct Phases Of Hormonally-Regulated Muscle Death In The Tobacco Hawkmoth Manduca Sexta. Journal of Insect Physiology, 55: 314-320.
Yu, J-G., Sewright, K., Hubal, M.J., Liu, J-X., Schwartz, L.M., Hoffman, E.P., and Clarkson, P.M. 2009. An Investigation Of Gene Expression In C2C12 Myotubes Following Simvastatin Application And Mechanical Strain. Journal of Atherosclerosis and Thrombosis, 16: 21-29.
Schwartz, L.M., Gao, Z., Brown, C., Parelkar S.S. and Glenn, H. 2009. Cell death in myoblasts and muscles. Methods Mol. Biol., 559: 313-332.
Wang. Z., Valavanis, C., Glenn, H., Sun, D., Seth, A., Karlstrom, K., Schwartz, L.M. 2009. Acheron Is A Phylogenetically-Conserved Regulation. Mechanisms of Development, 126: 700-709.
Hyldahl, R.D., O’Fallon, K.S., Schwartz, L.M., and Clarkson, P.M. 2010. Knockdown of metallothionein 1 and 2 does not affect atrophy or oxidant activity in cultured myotubes. Journal of Applied Physiology, 109: 1515-23.
Glenn, H., Wang, Z., and Schwartz, L.M. 2010. Acheron, A Lupus Antigen Family Member, Regulates Integrin Expression, Adhesion, And Motility In Differentiating Myoblasts. American Journal of Physiology - Cell Physiology, 298: C46-55.
Shao, R., Scully, Jr., S.J., Yan, W., Bentley, B., Mueller, J., Brown, C., Bigelow, C., and Schwartz, L.M. 2011. The Novel Lupus Antigen Protein Acheron Enhances The Development Growth Of Human Breast Cancer. International Journal of Cancer, oi: 10.1002/ijc.26015. [Epub ahead of print] .
Chul, K., Srivastava, S. Rice, M., Godenschwege, T.A., Bentley, B., Ravi, S., Shao, S., Woodard, C.T., and Schwartz, L.M. 2011. Expression Of Human Amyloid Precursor Protein In The Skeletal Muscles Of Drosophila Results In Age- And Activity-Dependent Muscle Weakness. BMC Physiology, April 25. doi: 10.1186/1472-6793-11-7.
Parelkar S.S., Cadena, J.G., Kim, C., Wang, Z., Sugal, R., Bentley, B., Moral, L., Ardley, H.C., and Schwartz, L.M. 201x. The Parkin-Like Human Homolog Of Drosophila Ariadne-1 (Hhari) Can Induce Aggresome Formation In Mammalian Cells And Is Immunologically Detectable In Lewy Bodies. Journal of Molecular Neuroscience, [Epub ahead of print] .
Fahrbach, S.E., Nambu, J.R. and Schwartz, L.M. 2012. Programmed cell death in insect neuromuscular systems during metamorphosis. In: Insect Molecular Biology and Biochemistry, L.I. Gilbert editor, pp 419-449. .