Lawrence M. Schwartz

Research Interests

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 remainder die by apoptosis. The genes we initially isolated from the ISMs appear to play key roles in this decision making process. Not only does this work enhance our understanding of myogenesis as a developmental problem, but it may also provide powerful tools for regulating the survival of myoblasts that are used for transplantation for gene therapy.

A second line of investigation in our laboratory focuses on the regulation of skeletal muscle atrophy. Age- and disease-induced atrophy represents a major clinical problem, yet little is know about the molecular mechanisms that underlie this is regulated. We have found that some of the genes that we initially isolated from moth skeletal muscle play key regulatory roles in vertebrate atrophy, and we are pursuing this line of investigation with the hope of identifying potential therapeutic targets.

Lastly, we have begun to examine the role of the ubiquitin/proteasome system in the regulation of neuron survival in both insects and mammals. Deregulation of this pathway is responsible for several forms of familial Parkinsonism. Working with mouse and human material, we are trying to understand not only why dopaminergic neurons are endangered in these diseases, but also why other cells appear to be spared.

Baystate Medical Center- UMass Amherst Biomedical Research Institute:
I have recently been appointed as the scientific director for the new Baystate Medical Center- UMass Amherst Biomedical Research Institute. The institute represents a true collaboration between the Baystate Medical Center, one of the largest teaching hospitals in the country, and the University of Massachusetts. Located in Springfield, the institute contains 17,000 square feet of newly renovated research space, complete with surgical suites, animal facilities and bench space for up to seventy investigators. In addition, another 25,000 square feet is being leased to biotechnology companies who want to collaborate with institute scientists and clinicians. An additional 33,000 square feet is available to meet future expansion needs. The goal of the institute is to facilitate translational research in order to hasten the development of medical treatments, diagnostic tests and medical devices.

Representative Publications

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 St¸hmer, 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.

Sun, D., Swaffield, J.C., Johnston, S.A., Milligan, C.E., Zoeller, T. and Schwartz, L.M. 1997. Identification of a phylogenetically conserved CAD family that is differentially expressed in the mouse nervous system. J. Neurobiol., 33: 877-890.

Cheng, L., Roemer, N., Smyth, K.-A., Belote, J., Nambu, J., and Schwartz, L.M. 1998. Cloning and characterization of Pros45, the Drosophila sug-1 proteasome subunit homolog. Molec. Gen. Genetics, 259: 13-20.

Barnes, N.Y., Li, L., Yoshikawa, K., Schwartz, L.M., Oppenheim, R.W. and Milligan, C.M. 1998. Increased production of amyloid precursor protein provides a substrate for Caspase-3 in dying motoneurons. J. Neurosci., 18: 5869-5880.

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.

Kuelzer, F., Kuah, K., Bishoff, S.J., Cheng, L., Nambu, J., and Schwartz, L.M., 1999. SCLP (Small Cytoplasmic Leucine-Rich Repeat Protein) Encodes a Novel Protein that is Dramatically Up-Regulated During te Programmed Death of Moth Skeletal Muscle. J. Neurobiol., 41: 482-494.

Valavanis, C., Nabor, S., and Schwartz, L.M. 2001. In Situ Detection of Dying Cells in Normal and Pathological Tissues. Methods in Cell Biology, 66: 393-415.

Valavanis, C., Hu, Y., Yang, Y., Osborne, B.A., Chouaib, S., Ashwell, J.A. and Schwartz, L.M. 2001. Model Cell Lines for the Study of Apoptosis in Vitro. Methods in Cell Biology, 66: 417-436.

Jones, M.E.E. and Schwartz, L.M. 2001. Not All Muscles Meet the Same Fate When They Die. Cell Biology International, 25: 539-545.

Wing, J.P., Schwartz, L.M. and Nambu, J.R. 2001. The RHG domains of Drosophila Reaper and Grim are essential for their distinct cell killing activities and functional interactions with DIAP1 and DIAP2. Mechanisms of Development, 102: 193-203.

Cascone, P.J. and Schwartz, L.M. 2001. Role of the 3' UTR in regulating the stability and translatability of death-associated mRNAs in moth skeletal muscle. Development, Genes and Evolution, 211: 397-405.

Shumway, L. and Schwartz, L.M. 2001. A Generalized 96 Well Format for Quantitative and Qualitative Monitoring of Altered Protein Expression and Activation in Cells. BioTechniques, 31: 996-1000.

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.