Neuromuscular Biology & Disease Group

"It makes all the difference whether you look at someone
as a risen ape or a fallen angel." ----Tom Burnam

Principal Investigator
JM

Group Members


Positions Available


Research Areas


Publications


Sponsors


















Bcl-2/Sca-1
Fig. 1. Bcl-2 and Sca-1 are
co-expressed in a rare subset of skeletal muscle cells in culture.


Jeffrey Boone Miller

Senior Scientist at Boston Biomedical Research Institute
Associate Professor of Neurology at Harvard Medical School
Tutor in Biochemical Sciences at Harvard University

B.S. Washington State University
Ph.D. University of California at Berkeley

Email:miller@bbri.org
Telephone: 617-658-7737
Mail: BBRI, 64 Grove Street, Watertown, MA 02472

Group Members.

Maggie Ardelt, B.A.
Mary Lou Beermann, B.S.
Mahasweta Girgenrath, Ph.D.
Vivek Vishnudas, Ph.D.

Positions Available.

No positions are available at this time.

Research Areas.


1. Apoptosis in neuromuscular biology & disease.

Apoptosis may play a role during muscle injury repair, the progression of pathology during muscle disease, and the loss of muscle mass with aging. In one series of experiments, we're examining the functions of cell death regulators, particularly those of the Bcl-2 family, in skeletal muscle. We use knock-out and transgenic assays, as well as disease models, to examine these issues. Our current and published work suggests that the Bcl-2 family members play an important role in the formation and growth of particular types of muscle cells (Dominov et al., 1998, 2001), and that inhibition of apoptosis can ameliorate pathology in laminin-alpha2-deficiency (Girgenrath et al., 2004; Dominov et al., 2005). Our goal is to develop a pharmaceutical treatment based on this knowledge.

2. Stem cells in adult skeletal muscle.
Recent work has shown that skeletal muscles contain a small number of multipotent stem cells whose progeny can make not only muscle but also other cell types such as blood and bone. We have proposed that Bcl-2 expression is a characteristic of these cells (e.g., Dominov et al., 1998); and the cell surface antigens Sca-1 and CD45 identify additional subsets (see Fig. 1.) (Girgenrath et al., 2005). We are currently developing methods to purify these adult stem cells and to test their multipotentiality with in vitro and in vivo assays. A long-term goal is determine the signals that control the growth and differentiation of these stem cells and to determine how they function in normal, injured, aging, and diseased muscle.

3. Developmental toxicology: Microarray analyses.
A number of environmental contaminants, such as PCBs and particular pesticides, appear to cause long-term behavioral deficits in animals and humans that have been exposed in utero. A promising approach to understanding how these toxicants influence their targets is to use DNA microarrays to identify toxicant-regulated genes. In collaboration with teams of scientists, headed by Dr. Peter Spencer, at the Center for Occupational and Environmental Toxicology at the Oregon Health & Science University (www.ohsu.edu/croet), we are using microarray technology to test hypotheses about how toxicants alter gene expression and function in embryonic and fetal neurons. (to top of page)

Selected Publications.

  • Miller, J. B. and Girgenrath, M. (2006) Role of apoptosis in neuromuscular diseases and potential usefulness of anti-apoptosis therapy. Trends Mol. Med. 12:279-286.
  • Dominov, J. A., Kravetz, A. J., Ardelt, M., Kostek, C. A., Beermann, M. L., Miller, J. B. (2005) Muscle-specific BCL2 expression ameliorates muscle disease in laminin {alpha}2-deficient, but not dystrophin-deficient, mice. Hum Mol Genet. 14(8):1029-40.
  • Girgenrath, M., Kostek, C. A., and Miller, J. B. (2005) Diseased muscles that lack dystrophin or laminin-alpha2 have altered compositions and proliferation of resident stem cells. BMC Neurol. Vol. 5, paper 7 (pp1-10)
  • Girgenrath, M., Dominov, J. A., Kostek, C. A., Miller, J. B. (2004) Inhibition of apoptosis improves outcome in a model of congenital muscular dystrophy. J Clin Invest. 114(11):1635-1639.
  • Nowak, J. A., Malowitz, J., Girgenrath, M., Kostek, C. A., Kravetz, A. J., Dominov, J. A., Miller, J. B. (2004) Immortalization of mouse myogenic cells can occur without loss of p16INK4a, p19ARF, or p53 and is accelerated by inactivation of Bax. BMC Cell Biol. 5(1):1-14.
  • Miller, J. B. and Emerson, C. P. Jr. (2003) Does the road to muscle rejuvenation go through notch? Sci. Aging Knowl. Environ. 48:pe34.
        Link to Abstract,  Link to Full Text
  • Lykke-Andersen, K, Schaefer, L., Menon, S., Deng, X.-W., Miller, J. B. and Wei, N. (2003). Disruption of COP9 subunit Csn2 in mouse causes deficient cell proliferation, accumulation of p53 and cyclin E, and early embryonic death. Mol. Cell. Biol. 23:6790-6797.
  • Pavlath, G. K., Dominov, J. A., Kegley, K. M., and Miller, J. B. (2003) Regeneration of skeletal muscles with altered timing of expression of the myogenic bHLH factor MRF4. Am. J. Pathol. 162:1685-1691.
  • Kostek, C., Dominov, J.A., and Miller, J.B. (2002) Upregulation of MHC class I accompanies, but is not required for, spontaneous myopathy in dysferlin-deficient SJL/J mice. Am. J. Pathol. 160:833-839.
  • Miller, J. B. (2001) Developmental biology of skeletal muscle. In: Disorders of Voluntary Muscle, 7th edition (Camb. U. Press) Eds. G. Karpati, R.C. Griggs & D. Hilton-Jones pp 26-41.
  • Dominov, J.A., Houlihan-Kawamoto C. A., Swap C. J., and Miller, J.B. (2001). Pro- and anti-apototic members of the Bcl-2 family in skeletal muscle: A distinct role for Bcl-2 in later stages of myogenesis. Dev. Dynam. 220:18-26.
  • Schaefer, L., Engman, H., and Miller, J. B. (2000). Coding sequence, chromosomal localization, and expression pattern of Nrf1: the mouse homolog of Drosophila erect-wing. Mammalian Genome 11:104-110.
  • Schaefer, L., Beermann, M. L., and Miller, J. B. (1999). Coding sequence, genomic organization, chromosomal localization, and expression pattern of the signalosome component Cops2: The mouse homologue of Drosophila alien. Genomics 56:310-316.
  • Miller, J. B., Schaefer, L., and Dominov, J. A. (1999) Seeking muscle stem cells. Curr. Top. Dev. Biol. 43, 191-219.
  • Dominov, J.A., Dunn, J.J., and Miller, J.B. (1998) Bcl-2 expression identifies an early stage of myogenesis and promotes clonal expansion of muscle cells. J. Cell Biol. 142:537-544
  • Zhu, Z. and Miller, J.B. (1997) MRF4 can substitute for myogenin during early stages of myogenesis. Dev. Dynam. 209:233-241.
  • Mei, L., Kachinsky, A. M., Seiden, J. E., Kuncl, R.W., Miller, J. B. and Huganir, R. L. (1996) Differential expression of PTP1D, a protein tyrosine phosphatase with two SH2 domains, in a slow and fast skeletal muscle fibers. Exp. Cell Res. 224:379-390.
  • Nikovits, W., Wang, G., Feldman, J. L., Miller, J. B., Wade, R., Nelson, L., and Stockdale, F. E. (1996) Isolation and characterization of an avian slow myosin heavy chain gene expressed during embryonic skeletal muscle fiber formation. J. Biol. Chem. 271:17047-53.
  • Dominov, J.A. and Miller, J.B. (1996) POU homeodomain genes and myogenesis. Dev. Genet. 19:108-118.
  • Block, N.E., Zhu, Z., Kachinsky, A.M., Dominov, J.A., and Miller, J.B. (1996) Acceleration of somitic myogenesis in embryos of myogenin promoter-MRF4 transgenic mice. Dev. Dynam. 207:382-394.
  • Miller, J.B. (1995) Making one cell from two. Nature 377:575-576.
  • Miller, J.B. and Boyce, F. (1995) Gene therapy by and for muscles. Trends Gen. 11:163-165.
  • Smith, T.H. and Miller, J.B. (1994) Somite subdomains, muscle cell origins, and the four muscle regulatory factor proteins. J. Cell Biol. 127, 95-105
  • Smith, T.H., Block, N.E., Rhodes, S.J., Konieczny, S.F. and Miller, J.B. (1993) A unique pattern of expression of the four muscle regulatory factors distinguishes somitic from embryonic, fetal, and newborn mouse myogenic cells. Development 117:1125-1133.
  • Miner, J.H., Miller, J.B., and Wold, B.J. (1992) Skeletal muscle phenotypes initiated by ectopic MyoD in transgenic mouse hearts. Development 114:853-860.
  • Miller, J.B. (1992) Myoblast diversity in skeletal myogenesis: How much and to what end? Cell 69:1-3.
  • Block, N.E. and Miller, J.B. (1992) MRF4, a myogenic helix-loop-helix protein, produces multiple changes in the myogenic program of BC3H-1 cells. Mol. Cell. Biol. 12:2484-2492. (to top of page)
Research Sponsors.
Our work is supported by:
Muscular Dystrophy Association (www.mdausa.org)
National Heart, Lung, & Blood Institute (www.nhlbi.nih.gov)
National Institute of Arthritis & Musculoskeletal & Skin Diseases
(www.niams.nih.gov)
National Institute of Environmental Health Sciences (www.niehs.nih.gov)
U. S. Department of Agriculture (www.reeusda.gov/nri) (to top of page)