Previous and Current Research

Regeneration is a process that completely re-grows lost structures from a tissue stump. The zebrafish has a very extensive ability to regenerate lost compound structures such as appendages and organs, and the goal of my research is to understand how the zebrafish activates and regulates molecular programs that allow it to regenerate these structures. Toward this aim, my groups is working on several genes that we believe are involved in one or more phenomena in regenerating fin appendages and heart: cell proliferation, tissue patterning, cell differentiation and tissue growth control.

Two hallmarks of epimorphic regeneration are extensive cell proliferation and the reactivation of genes involved in embryonic development. The gene simplet/family with sequence similarity 53-member b (smp/fam53b) is expressed in regenerating tissue that is highly proliferative. This gene is conserved in vertebrate species, but nothing is known about how the gene functions. When we knockdown of smp in regenerating caudal fins, we observe reduced regenerative outgrowth and a significant reduction of proliferating cells, suggesting that smp controls a pro-regeneration cell proliferation program. In addition to the involvement of smp in cell proliferation, we observe that the presence of this gene is also involved in the regulation of specific pro-regeneration genes, namely, msxb and sonic hedgehog, two genes required for appendage regeneration. From our work on the molecular mechanism of smp, we have determined that it directly regulates the Wnt signal transduction pathway by mediated β-catenin nuclear localization. My group is currently investigating how smp is regulating this transduction pathway in regeneration and development.

The gene midkine-related growth factor a (mdka) is highly expressed early during the regeneration process both in the fish heart and fin appendage, and its expression remains as structural regeneration proceeds. Morpholino-mediated knockdown and transgenic overexpression of a dominant-negative construct of mdka in regenerating fins result in a reduction in the regenerative outgrowth, indicating that it has an important role in the regulation of formation of new tissue. We are currently determining which tissue(s) are affected first and the molecular mechanism(s) through which mdka functions. Because mdka is an extracellular ligand, and it is unclear what receptors are involved in binding mdka in regenerating tissues, we are working to identify the appropriate transmembrane receptors.

From a forward genetic screen for fish that have lost their ability to regenerate, we are characterizing the larval mutant knörf. My group is currently characterizing the cellular and molecular biology associated with lack of regeneration and mapping (locating) the mutation on chromosome 4 to find the gene responsible for the mutant phenotype.

In addition to researching the mechanisms involved in the early stages of regeneration, we are also studying the mechanisms involved in patterning and growth control. Regenerating zebrafish fins faithfully pattern and regenerate to the same size as the original lost appendage. We have uncovered a molecular mechanism that is involved in the regulation of this growth. Interfering with this mechanism results is a regenerate that grow twice the size as the normal fin and lack the segment joints. We are currently working to identify which tissue(s) are directly responsible for the enhance growth and discover the mechanism(s) underlying the enhanced growth phenotype.

Lastly, we have identified additional genes that are active in organ and appendage regeneration from various microarray screens and comparisons of regenerating tissues. Thus, we are testing whether these genes are required for regeneration and, if so, how they are involved in cell proliferation, tissue patterning, cell differentiation and tissue growth control of regenerating zebrafish organs and appendages.

Future Goals and Projects

The fundamental goal of regenerative medicine is to replace damaged or lost tissues with healthy tissues. The identification of the genes—and their molecular mechanisms—involved in epigenetic regeneration can offer pharmaceutical targets for therapies designed to restore function to damaged organs and appendages. Toward this aim, we are starting to collaborate with different clinical research groups in the CRTD network to determine whether the genes that we have identified potentiate repair and regeneration of mammalian tissues.

Group Members

List of group members

Selected Publications

Antos CL and Brand M, “Regeneration of Organs and Appendages in Zebrafish: A Window into Underlying Control Mechanisms” in Encyclopedia of Life Sciences (2010) John Wiley & Sons, Ltd: Chichester www.els.net [DOI: 10.1002/9780470015902.a0022101]

Antos CL and Tanaka EM, Book Chapter “Vertebrates that Regenerate as Models for Guiding Stem Cells” in The Cell Biology of Stem Cells, Eds. Meshorer E & Plath K, Landes Bioscience. Landes Bioscience (2010) Advances in Experimental Medicine and Biology Vol. 695: 184-214.

Rojas-Munoz A, Rajadhyksha S, Gilmour D, van Bebber F, Antos C, Rodriguez Esteban C, Nüsslein-Volhard C, Izpisua Belmonte JC., ErbB2 and ErbB3 regulate amputation-induced proliferation and migration during vertebrate regeneration. (2009) Dev. Biol. 327: 177-190.

Kizil C, Otto GW, Geisler R, Nüsslein-Volhard C, Antos CL. Simplet controls cell proliferation and gene transcription during zebrafish caudal fin regeneration. Dev Biol. (2009) Vol. 325: 329-340.

Luckey SW, Mansoori J, Fair K, Antos CL, Olson E, Leinwand LA., Blocking cardiac growth in hypertrophic cardiomyopathy induces cardiac dysfunction and decreased survival only in males. (2007) American Journal of Physiology Heart Circulation Physiology 292: H838-H845.

Antos CL (Co-first authorship), Lopez-Rodriguez C, Shelton JM, Richardson JA, Lin F, Novobrantseva TI, Bronson RT, Igarashi P, Rao A, and Olson EN., Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression (2004) Proceedings of the National Academy of Sciences U.S.A. 101: 2392-2397.

Antos CL, McKinsey TA, Dreitz M, Hollingsworth LM, Zhang CL, Schreiber K, Rindt H, and Olson EN., Blockade to Cardiomyocyte Hypertrophy by Histone Deacetylase Inhibitors (2003) Journal of Biological Chemistry 278: 28930-28937.

Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, and Olson EN., Class II Histone Deacetylases Act as Signal-responsive Repressors of Cardiac Hypertrophy. (2002) Cell 110: 479-488.

Antos CL, McKinsey TA, Frey N, Kutschke W, McAnally J, Shelton JM, Richardson JA, Hill JA, and Olson EN., Activated Glycogen Synthase [Kinase]-3b Suppresses Cardiac Hypertrophy in vivo. (2002) Proceedings of the National Academy of Sciences U.S.A.99: 907-912.

Antos CL, Frey N, Marx SO, Reiken S, Gaburjakova M, Richardson JA, Marks AR, and Olson EN., Dilated Cardiomyopathy and Sudden Death Resulting from Constitutive Activation of Protein Kinase A. (2001) Circulation Research 89: 997-1004.