Michael Lampson

cell division, intracellular signaling, meiosis

Overview

Cell division is the process by which a cell creates two daughter cells, each with a full copy of the genome.  Failure of this process leads to cells with either an incomplete genome or extra copies of part of the genome, a condition known as aneuploidy that is best avoided.  The genetic material is organized by packaging into chromosomes, each of which is replicated before a cell divides.  In mitotic cell division the two copies of each chromosome, referred to as sisters, are physically segregated with exquisite precision so that each daughter cell received exactly one copy of each sister.  In this way the integrity of the genome is maintained over billions of cell divisions that occur during the lifetime of an organism.  Meiotic cell division is a variation on this process, in which two consecutive cycles of cell division, without an intervening round of replication, produce gametes with half the normal number of chromosomes.  The overall goal of our research is to understand the mechanisms that ensure accurate chromosome segregation in both mitotic and meiotic cell division.  Two current research directions are highlighted below.

 Interactions between kinetochores and spindle microtubules

Regulation of kinetochore-microtubule interactions is crucial for accurate chromosome segregation and maintenance of genome integrity.  We use a variety of experimental approaches to manipulate enzymatic activities, such as kinases, at kinetochores and to measure the effects of these perturbations in living cells.  Examples include chemically-induced dimerization to recruit activities to kinetochores with precise temporal control, FRET-based biosensors that report on phosphorylation changes with high temporal and spatial resolution in live cells (Figure 1), and photoactivatable fluorescent proteins to measure protein dynamics.  We are also reconstituting a diffusion based signaling mechanism for a key mitotic kinase, Aurora B, from purified components in vitro.  We exploit these experimental tools to develop and test mathematical models for kinase signaling and microtubule dynamics.  

Figure 1.  A diffusion-based phosphorylation gradient emanating from centromeres.  Left image: Chromosomes (green) are arranged around a monopolar mitotic spindle, with centromeres (red) oriented towards the center.  Right image: A FRET-based biosensor for Aurora B activity shows high phosphorylation (blue) near the centromeres and low phosphorylation (yellow) at a distance; centromeres are labeled green.  Adapted from Wang et al. 2011.

Mechanisms of meiotic drive

Chromosome segregation is generally assumed to be random: as long as the sister chromosomes segregate in opposite directions, it doesn’t matter which sister goes in which direction.  In meiotic cell divisions, however, segregation is not always random, in violation of Mendel’s First Law.  Female meiosis in mammals and many other organisms produces one egg from two cycles of division, and the rest of the chromosomes are discarded.  Therefore, there is a strong evolutionary drive (meiotic drive) for a chromosome to make it into the egg.  Nonrandom segregation has been documented genetically, and has significant consequences for centromere and karyotype evolution and for speciation.  Despite the importance of the phenomenon, the mechanistic basis is mysterious.  We are using Robertsonian fusions in mouse oocytes (Figure 2) as a model to understand the cell biological mechanisms underlying nonrandom chromosome segregation, how the direction of drive is determined, and (most intriguingly) how it can reverse, leading to rapid and dramatic changes in karyotype. 

Figure 2.  Trivalent chromosome in meiosis I.  Image shows a mouse oocyte heterozygous for a Robertsonian fusion of chromosomes 6 and 16, fixed in meiosis I and stained for kinetochores (red) and DNA (green).  The trivalent, which forms when the fusion pairs with the two homologous unfused chromosomes, is positioned off the metaphase plate.  Inset is a magnification of the trivalent.  Schematic shows the chromosome organization within the trivalent.