Monica Colaiácovo

Department of Genetics
Harvard Medical School
New Research Building, Room 334
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: (617) 432-6543
Fax: (617) 432-7663
Email: mcolaiacovo@genetics.med.harvard.edu
Web Page: The Colaiácovo Lab Page
4 postdoctoral fellows, 1 graduate student

We are interested in understanding the mechanisms underlying faithful chromosome inheritance during meiosis. To segregate properly, chromosomes must undergo a series of steps during the first meiotic division, including (1) pairing with their homologous partners, (2) formation of a proteinaceous structure known as the synaptonemal complex (SC) along paired and aligned homologous chromosomes, and (3) completion of meiotic recombination leading to physical attachments (chiasmata) between homologs. Errors in pairing, synapsis, or recombination ultimately lead to chromosome non-disjunction with disastrous consequences for the embryo resulting in miscarriages and birth defects such as Down syndrome.

Our focus is on investigating the roles and the macromolecular assembly of the SC, a structure at center stage during meiosis, whose functions are poorly understood and a matter of much debate despite its ubiquitous presence from yeast to mammals. To study this structure we are using the nematode C. elegans, an experimental system especially amenable to coupling the application of abundant genetic, biochemical and molecular biology tools to powerful cytological approaches. The germline accounts for more than half of the cells in the adult worm and its nuclei are distributed throughout the gonad in a defined order, correlating with the sequential stages of classical meiosis. High-resolution 3-D imaging of meiotic chromosomes can be carried out in the context of a well preserved nuclear architecture, and pairing between homologs can be monitored by fluorescence in situ hybridization (FISH). Microarray technology applied to the C. elegans genome has led to the identification of meiotic gene candidates with germline-enriched expression. Techniques such as RNA-mediated interference (RNAi) and PCR-based screens for deletion alleles allow for assessment of the function of germline-active genes.

Recent identification of three SC components (SYP-1, SYP-2, and SYP-3) coupled with well-established reagents and assays allow us to address the following questions in the lab: How do the SYP proteins assemble to form the SC? What other components are required for synapsis? What are the functions of this structure? Is there a system set up to monitor appropriate assembly and disassembly of the SC?

To address these questions we are examining the interactions among the SC components by classical biochemical procedures, two hybrid analysis and immuno-electron microscopy. In addition, we are identifying new components required for synapsis by continuing our RNAi-based screen for SC components coupled to two-hybrid screens and the identification of co-immunoprecipitated proteins. Ultimately, we will determine the role of candidate SC components in forming the SC structure and their effects on crossover recombination and meiotic progression.

References:

• Colaiácovo, M. P. (2006) The many facets of SC function during C. elegans meiosis. Chromosoma 115: 195-211.
• Whetstine, J.R., Nottke, A., Lan, F., Huarte, M., Smolikov, S., Chen, Z., Spooner, E., Li, E., Zhang, G., Colaiácovo, M., and Shi, Y. (2006) Reversal of Histone Lysine Trimethylation by the JMJD2 Family of Histone Demethylases. Cell 125: 467-481.
• Egydio de Carvalho, C. and Colaiácovo, M.P. (2006) SUMO-mediated regulation of synaptonemal complex formation during meiosis. Genes & Development 20: 1986-1992.
• Smolikov, S., Eizinger, A., Schild-Prufert, K., Hurlburt, A., McDonald, K., Engebrecht, J., Villeneuve, A.M. and Colaiácovo, M.P. (2007) SYP-3 restricts synaptonemal complex assembly to bridge paired chromosome axes during meiosis in C. elegans. (in press)