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 activity-dependent control of muscle gene expression.

Nerve-induced muscle activity plays a critical role in formation of the neuromuscular junction, directing muscle fiber type specification (fast vs slow) and maintaining muscle mass and functional properties in the adult. We recently found that activity-dependent gene regulation in muscle is mediated by an HDAC4:Dach2:myogenin signal transduction cascade. Interestingly we found that HDAC4 is not only necessary for denervation-dependent gene induction but also denervation-dependent gene suppression. HDAC4 mediates gene suppression in collaboration with MEF2 and recruitment to MEF2 elements within muscle gene promoters. In contrast, HDAC4 activates muscle gene expression by suppressing expression of Dach2 and MITR that function as myogenin gene co-repressors. Relief of myogenin suppression allows it to activate muscle gene expression. Interestingly, we found that an HDAC4/myogenin positive feedback loop is necessary for coordinating the diverse patterns of gene expression underlying denervation-driven muscle phenotypic changes. Our goals are to further 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.

An HDAC4/myogenin positive feedback loop and its regulation of downstream genes in innervated and denervated muscle Bold is used to represent increased expression, levels or activity.

Our research in the nervous system focuses on two areas: 1) optic nerve regeneration and 2) retina 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. This type of strategy was used to show that KLF6/7 transcription factors are necessary for optic nerve regeneration. Our goals are to further define the signaling molecules necessary for optic nerve regeneration in fish and use this information to suggest strategies for improving CNS regeneration in mammals.

KLF6/7 are necessary for optic axon regeneration. Following optic nerve lesion, morpholino-modified antisense oligonucleotides targeting KLF6 and 7 were applied to the optic nerve stump for 1 day. Four days later retinas were isolated and placed in explant culture to assay optic axon regeneration. Blocking KLF6/7 expression dramatically blocked optic axon regeneration.

In addition to axonal regenerating, fish also can regenerate a damaged retina. We have found 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. In addition, microarray screens have identified a large number of genes regulated during retina regeneration. One such gene is the basic helix loop helix transcription factor, Ascl1a. We recently found that Ascl1a induction is necessary for Muller glia dedifferentiation and retina regeneration. Our goals are to identify genes that stimulate Muller glia dedifferentiation, allowing them to function as retinal stem cells. These genes may suggest ways of directing mammalian Muller glia to adopt a stem cell function that could then contribute to retinal repair following disease or injury.

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.

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.

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.

Suhr, S. T., Ramachandran, R., Fuller, C. L., Veldman, M. B., Byrd, C. A. and Goldman, D. Highly-restricted, cell-specific expression of the simian CMV-IE promoter in transgenic zebrafish with age and after heat shock. Gene Expr. Pattern, 2008 ePub ahead of print doi: 10.1016/j.gp.2008.07.002.

Tang, H., Macpherson, P., Marvin, M., Meadows, E., Klein, W. H., Yang, X.-J. and Goldman, D. An HDAC4/myogenin positive feedback loop coordinates denervation-dependent gene induction and suppression. Mol. Biol. Cell. In Press, 2008.