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Christopher Antos
Understanding the cellular and molecular biology of regeneration of the heart and the fin appendage of zebrafish
Previous and current research
Epimorphic regeneration is a process that completely regrows lost structures from an anatomically complex stump. The goal of my research is to understand how the zebrafish activates and regulates epimorphic regeneration programs. To accomplish this goal, I have performed screens for mutant adult and larval fish that fail to regenerate the caudal fin properly. From these screens, I have several larval and adult mutants that display either no regeneration, partial regeneration or mispatterned regeneration. My group is currently characterizing the cellular and molecular phenotypes associated with these mutations and mapping (locating) the mutations in the genome to find the genes responsible for the mutant phenotypes.
In addition to using mutagenesis screens, I have undertaken microarray profiling to identify genes that are active during the regeneration of the fin appendage and the heart. The microarrays are yielding data that are contributing to candidate-based discoveries.
One of the hallmarks of epimorphic regeneration is extensive cell proliferation. It is a prerequisite for accumulating enough cells so that these cells can contribute to the formation of new tissue. The gene fam53b (family with sequence similarity 53-member b) is expressed in regenerating tissue that is highly proliferative. Furthermore, knockdown of fam53b in regenerating caudal fins results in reduced regenerative outgrowth and a significant reduction of proliferating cells, suggesting that fam53b controls a pro-regeneration cell proliferation program. My group is currently investigating the biological role that fam53b has in controlling cell proliferation. In addition to the involvement of fam53b 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 shh, two genes required for the regeneration of the caudal fin.
In addition to fam53b in regeneration, my group is researching the role of other genes in the regeneration process. 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 on as structural regeneration proceeds. Knock down of mdka results in a reduction in the regenerative outgrowth of the fin, indicating that it has an important role in the regulation of formation of new tissue. Because mdka is a extracellular ligand, we are working to identify the appropriate transmembrane receptor and to test its importance in the regeneration process.
Future prospects and goals
The fundamental goal of regenerative medicine is to replace damaged or lost tissues with healthy tissue. The identification of the genes (and their molecular mechanisms) involved in epigenetic regeneration can offer pharmaceutical targets for therapies that restore healthy tissue.
My goal is to get the genes involved in the initiation and maintenance of pro-regeneration signals and to use these genes to understand the cellular and molecular biology of the epimorphic regeneration. To identify these genes, I have taken two complementary approaches: forward genetic mutagenesis screens (phenotype-based approach) and microarray screens (candidate-based approach). From these approaches, I have isolated fish that harbor genetically heritable regeneration phenotypes, and I have identified genes that (based on reverse genetic knockdown experiments) are required for proper regenerative growth. Present and future projects include characterizing the phenotypes and the mutated genes of the confirmed mutants, as well as researching the mechanisms of the highly expressed genes detected by the microarrays.
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Selected publications
Kizil C, Otto GW, Geisler R, Nüsslein-Volhard C, Antos CL, Simplet controls cell proliferation and gene transcription during zebrafish caudal fin regeneration. (2009) Developmental Biology 235: 329-340.
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) Developmental Biology 327: 177-190.
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.
Xing W, Zhang TC, Cao D, Wang Z, Antos CL, Li S, Wang Y, Olson EN, Wang DZ., Myocardin induces cardiomyocyte hypertrophy. (2006) Circulation Research 98: 1089-1097.
Lopez-Rodriguez C, Antos CL, 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.