Daniel Goldman, Ph. D.
Research Professor, MBNI
Professor, Department of Biological Chemistry

5045 BSRB
109 Zina Pitcher PL
Ann Arbor , MI 48109-2200

neuroman@umich.edu

734-936-2057

Current Research Interests:

The Goldman lab studies muscle and nerve. Our muscle research focuses on two areas: 1) activity-dependent control of muscle gene expression and 2) muscle development and dedifferentiation.

Muscle activity plays a critical role in shaping the neuromuscular junction during development and maintaining muscle mass and functional properties in the adult. Our research has led to the identification of activity-dependent control elements within muscle-specific gene promoters and the identification of some of the proteins that bind these elements. Our goals are to define the signal transduction cascades that confer activity-dependent regulation on muscle gene expression and use this information to improve muscle function following damage or disease.

Muscle cells engineered to express GFP from the nAChR gamma-subunit promoter.
Nuclei are stained blue with DAPI.

Muscle was thought to be an irreversibly differentiated tissue. However, we have recently demonstrated that differentiated mammalian muscle, in tissue culture, can be induced to dedifferentiate by forcing differentiated nuclei back into the cell cycle. Some of these nuclei bud from the myofiber along with some cytoplasm and generate multipotent cells. Our goals in this project are to understand the mechanisms of muscle dedifferentiation and harness these mechanisms for muscle and non-muscle tissue repair.

PCNA staining (pink) identifies myotube nuclei
that have re-entered the cell cycle.

Our research in the nervous system focuses on two areas: 1) optic nerve regeneration and 2) retinal regeneration.

Fish posses the remarkable ability to regenerate their CNS following damage. We are using zebrafish as a model system to identify mechanisms for CNS repair following damage or disease. We have created transgenic zebrafish that harbor the a1 tubulin gene’s promoter driving GFP expression. This transgene is expressed in the developing and regenerating fish CNS. Promoter mutagenesis has identified cis regulatory elements that mediate its induction during optic nerve regeneration. Microarray analysis of genes specifically induced in retinal ganglion cells identified transcription factors and signaling molecules induced during optic nerve regeneration. Antisense-based knockdown of gene expression is being used to ascertain the functional significance of these molecules during optic nerve regeneration.

Optic nerve crush induces endogenous tubulin (top) and
transgene (bottom) expression in retinal ganglion cells.

In addition to axonal regenerating, fish also can regenerate a damaged retina. We are testing the idea that Muller glia dedifferentiate following retinal damage to generate multipotent progenitors that can then repopulate the damaged retina and restore its function. Lineage mapping and targeted cell ablation are being used to study the role of Muller glia in retinal regeneration.

Retinal damage induces transgene expression in Muller glia.

Retina Regeneration “Retina Regeneration” is an animation depicting our current understanding of retina regeneration in zebrafish produced by Harvey Goldman. Click on the image to play.

A large-scale genetic screen for mutations affecting CNS development and regeneration is also underway in the lab. This is a reporter-assisted screen in which we look for changes in transgene GFP expression in chemically mutagenized fish. We have identified over a dozen mutations that affect neural cell proliferation and differentiation. It is anticipated that many of these mutations will also impact CNS regeneration in the adult. Our goal here is to clone the mutant genes and characterize their function in the developing and regenerating CNS.

Selected Publications:

Fausett, B. and Goldman, D. A role for a1 tubulin-expressing Muller glia in regeneration of the injured zebrafish retina. J. Neurosci. 2006: 26:6303-6313.

Tang, H. and Goldman, D. Activity-dependent gene regulation in skeletal muscle is mediated by a histone deacetylase (HDAC)-Dach2-myogenin signal transduction cascade. Proc. Natl. Acad. Sci. USA 2006; 103:16977-16982.

Buchner, D. A., Su, F., Yamaoka, J. S., Kamei, M., Shavit, J. A., Barthel, L. K., McGee, B., Amigo, J. D., Kim, S., Hanosh, A. W., Jagadeeswaran, P., Goldman, D., Lawson, N. D., Raymond, P. A., Weinstein, B. M., Ginsburg, D. and Lyons, S. E. pak2a mutations cause cerebral hemorrhage in redhead zebrafish. Proc. Natl. Acad. Sci. USA 2007; 104:13996-14001.

Veldman, M. B., Bemben, M. A., Thompson, R. C. and Goldman, D. Gene expression analysis of zebrafish retinal ganglion cells during optic nerve regeneration identifies KLF6a and KLF7a as important regulators of axon regeneration. Developmental Biology, 2007; 312:596-612.

Fausett, B. V., Gumerson, J. D. and Goldman, D. The proneural gene ascl1a is required for retina regeneration. J. Neurosci. 2008; 28:1109-1117.