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Molecular and Cellular Biology, July 2009, p. 3746-3753, Vol. 29, No. 13
0270-7306/09/$08.00+0     doi:10.1128/MCB.01684-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Topoisomerase II{alpha} Is Required for Embryonic Development and Liver Regeneration in Zebrafish{triangledown}

Michael Dovey, E. Elizabeth Patton,{dagger} Teresa Bowman, Trista North,{ddagger} Wolfram Goessling,§ Yi Zhou, and Leonard I. Zon*

Stem Cell Program and Hematology/Oncology, Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts

Received 30 October 2008/ Returned for modification 19 December 2008/ Accepted 20 March 2009

Topoisomerases solve the topological problems encountered by DNA throughout the lifetime of a cell. Topoisomerase II{alpha}, which is highly conserved among eukaryotes, untangles replicated chromosomes during mitosis and is absolutely required for cell viability. A homozygous lethal mutant, can4, was identified in a screen to identify genes important for cell proliferation in zebrafish by utilizing an antibody against a mitosis-specific marker, phospho-histone H3. Mutant embryos have a decrease in the number of proliferating cells and display increases in DNA content and apoptosis, as well as mitotic spindle defects. Positional cloning revealed that the genetic defect underlying these phenotypes was the result of a mutation in the zebrafish topoisomerase II{alpha} (top2a) gene. top2a was found to be required for decatenation but not for condensation in embryonic mitoses. In addition to being required for development, top2a was found to be a haploinsufficient regulator of adult liver regrowth in zebrafish. Regeneration analysis of other adult tissues, including fins, revealed no heterozygous phenotype. Our results confirm a conserved role for TOP2A in vertebrates as well as a dose-sensitive requirement for top2a in adults.

* Corresponding author. Mailing address: Children's Hospital Boston, Karp Family Research Building Room 7211, 1 Blackfan Circle, Boston, MA 02115. Phone: (617) 919-2069. Fax: (617) 730-0222. E-mail: zon{at}enders.tch.harvard.edu

{triangledown} Published ahead of print on 20 April 2009.

{dagger} Present address: Edinburgh Cancer Research Centre & MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh, United Kingdom.

{ddagger} Present address: Department of Experimental Pathology, Beth Israel Deaconess Medical Center, Boston, MA.

§ Present address: Genetics and Gastroenterology Divisions, Brigham and Women's Hospital Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Harvard-MIT Division of Health Science and Technology, Harvard Stem Cell Institute, Boston, MA.

Molecular and Cellular Biology, July 2009, p. 3746-3753, Vol. 29, No. 13
0270-7306/09/$08.00+0     doi:10.1128/MCB.01684-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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