Meiotic prophase chromosome dynamics
My research seeks to understand the fundamental, yet long mysterious, cellular mechanisms that drive chromosome dynamics during the differentiation of sex cells (gametes).
A critical feature of gamete differentiation is chromosome reduction; each gamete must contain exactly half the chromosome complement of its progenitor (parent) cell. If chromosomes fail to segregate properly during gamete formation, gametes and the offspring they generate are aneuploid (contain an improper number of chromosomes).
How are chromosome complements properly divided? At the onset of the specialized cell division cycle called meiosis, each chromosome somehow identifies and specifically associates with its homologous partner. This nuclear reorganization process culminates in paired homologous chromosomes that are joined along their lengths by a proteinaceous structure, the synaptonemal complex (SC), and each capable of undergoing crossover recombination. Each of these steps, chromosome pairing, SC assembly (synapsis) and crossover recombination, are conserved features of meiosis that ensure accurate chromosome reduction: Together, these steps allow homologous chromosomes to orient with respect to one another and thereby segregate toward opposite spindle poles at the first meiotic division. Despite over a century of observing meiotic chromosome pairing and synapsis in diverse organisms, the molecular mechanisms underlying these fundamental meiotic chromosomal events are still unknown. How do homologous chromosomes identify one another? How is this initial recognition between chromosomes reinforced? How is homolog recognition coordinated with SC assembly, such that synapsis occurs specifically between paired chromosomes?
My research has begun to investigate these questions by screening for factors that regulate chromosome pairing and synapsis in budding yeast. A genetic screen for factors that prevent synapsis in the absence of homolog pairing revealed several regulators of SC assembly. Two proline isomerase proteins, Fpr3 and Rrd1, appear to independently regulate the spatial distribution of SC components when homologous chromosome pairing is delayed or defective. The proline isomerase activity of Fpr3 and Rrd1 raises the possibility that the capacity of synapsis proteins to assemble SC is under regulation by chaperone proteins in the nucleus. My screen also uncovered a surprising role for the E3 SUMO ligase protein, Zip3 (previously known for its role in promoting synapsis) in preventing SC assembly on chromosomes. When polycomplex formation is compromised and Zip3 activity is missing, (as in a zip3 fpr3 double mutant), SC components polymerize on chromosomes, independent of homolog alignment.
Interestingly, synapsis in zip3 fpr3 nuclei initiates exclusively from centromeric chromosomal regions. This suggests a role for centromeres in coordinating major meiotic chromosomal events and draws an interesting parallel between yeast centromeres and C. elegans Pairing Centers. (In C. elegans, homologous pairing and synapsis is coordinated predominantly at a single, cis-acting, site on each chromosome.) As Zip3 colocalizes with the SC structural component, Zip1, at centromere regions prior to homologous chromosome pairing, perhaps the critical regulatory role of Zip3, Fpr3 and Rrd1 pathways is to prevent synapsis initiation from the centromere of a chromosome pair until homolog recognition has successfully occurred.
A fundamental goal of the lab’s future research is to understand how the Fpr3, Rrd1 and Zip3 proteins regulate SC assembly and, on a broader level, to understand the molecular signals that coordinate recombination, homolog pairing and synapsis.
Funding: National Institutes of Health
Current lab members: Karen Voelkel-Meiman, Pritam Mukherjee, Lina Yesehak, Louis Taylor, Cassandra O’Curran.