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Cell Division and Intracellular Signaling
Our research focuses on molecular mechanisms that maintain genomic integrity during cell division. The replicated chromosomes are physically segregated at each division to create two genetically identical daughter cells. Segregation errors lead to loss or gain of whole chromosomes in the daughter cells, or aneuploidy, which is strongly associated with human cancer and developmental disease. A complex and highly dynamic cellular machinery ensures accurate chromosome segregation, with many events occurring on minute or second timescales. While many of the key components have been identified, we now face the challenge of understanding how the system is controlled. Using high resolution light microscopy, combined with molecular perturbations introduced by RNAi or with small molecule inhibitors, we will examine key processes in cell division in real time in the context of living mammalian cells. Mitotic kinases are critical for the regulation of these processes, and we are developing probes based on fluorescence resonance energy transfer (FRET) to examine kinase signaling networks at specific intracellular structures, such as centromeres and spindle poles, in living cells.
A core project in the lab is to examine signaling at the centromere, the site on each chromosome that attaches to the mitotic spindle. Accurate chromosome segregation requires that each replicated chromosome pair attaches to spindle microtubules in the correct configuration (see figure) so that sister chromosomes are pulled in opposite directions at anaphase. Attachment errors must be (1) detected, to activate the spindle checkpoint, and (2) corrected before anaphase onset. Both of these processes require that correct and incorrect attachments be distinguished. We will test the hypothesis that this distinction is made through differential signaling by mitotic kinases at individual centromeres. Starting with this project, we hope to develop models for site-specific signaling neworks that control critical processes in cell division.
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