Couples, pairs, and clusters: mechanisms and implications of centromere associations in meiosis

Abstract

Observations of a wide range of organisms show that the centromeres form associations of pairs or small groups at different stages of meiotic prophase. Little is known about the functions or mechanisms of these associations, but in many cases, synaptonemal complex elements seem to play a fundamental role. Two main associations are observed: homology-independent associations very early in the meiotic program-sometimes referred to as centromere coupling-and a later association of homologous centromeres, referred to as centromere pairing or tethering. The later centromere pairing initiates during synaptonemal complex assembly, then persists after the dissolution of the synaptonemal complex. While the function of the homology-independent centromere coupling remains a mystery, centromere pairing appears to have a direct impact on the chromosome segregation fidelity of achiasmatic chromosomes. Recent work in yeast, Drosophila, and mice suggest that centromere pairing is a previously unappreciated, general meiotic feature that may promote meiotic segregation fidelity of the exchange and non-exchange chromosomes.

Figure 1. Centromere behavior in budding yeast and mouse spermatocytes in meiotic prophase

Two homologous pairs of chromosomes (blue and red) each one comprised of two sister chromatids are represented at different stages of meiosis I in budding yeast and mouse spermatocytes. Budding yeast begins meiosis with the centromeres clustered next to the spindle pole body (the Rabl conformation) which is common in many other organisms, while in mouse spermatocytes the centromeres appear more dispersed with some evidence for limited associations at meiotic entry. In yeast, the centromeres disperse from the Rabl cluster and form non-homologous couples (CEN coupling), in mice, however, no evidence of coupling has been seen. In most organisms, including yeast and mice, at the pachytene stage, the homologous chromosomes are aligned along their length forming a proteinaceous structure between them called the synaptonemal complex (synapsis). At the end of prophase I the synaptonemal complex along the arms disassembles, but persists at the centromeres. In metaphase I the centromeres of the homologous chromosomes are pulled towards opposite poles, in preparation for chromosome segregation that will take place in anaphase (not shown).

Figure 2. Model of budding yeast synaptonemal complex

The synaptonemal complex is responsible for tight chromosome synapsis during the pachytene stage of meiosis. It appears “ladder like”; the chromosome axes of the two homologous chromosomes (colored blue) are called lateral elements (LEs) at this stage. The chromatin loops out (colored yellow) from the chromosome axes. The LEs become connected by transverse filaments (the steps of the ladder), which in budding yeast are constituted by the protein Zip1. Recent data suggest that polymeric SUMO chains (blue ovals) play a role on synaptonemal complex formation by binding to both Zip1 and the chromosome axis protein Red1 (red square). Zip1 binds SUMO noncovalently, Red1 can either form covalent SUMO conjugates or bind it non-covalently (not represented). SUMO interactions with other synaptonemal complex elements, like Ecm11, probably play an important role in synaptonemal complex formation and dynamics (not represented). Figure 3. Model of centromere associations and synaptonemal complex formation

Figure 3. Models of centromere associations and synaptonemal complex formation in budding yeast

Two pairs of homologous chromosomes are represented (red and blue), each one composed of two sister chromatids. A) At leptotene (early prophase), coupling occurs in a homology independent fashion, usually between non-homologous centromeres. Coupling coincides with the beginning of recombination and synaptonemal complex formation. Centromere coupling is unstable due to the interplay of Mec1/PP4 on Zip1 phosphorylation status; phosphorylation of Zip1 blocks coupling. B) Synaptonemal complex formation is thought to start at sites of crossover initiation and spread along the chromosomes. SC initiated in this manner might propagate to centromeres, promoting the pairing of homologous centromeres and forming long stretches of synaptonemal complex with the centromeric region at one end. C) It has also been proposed that synaptonemal complex formation may start from the centromeres, which are rich in the central element component Zip1. D) In the pachytene stage full chromosome synapsis has been achieved. The pairing between the homologous centromeres is likely stabilized by the synaptonemal complex. Zip1 has a fundamental role in both bridging synaptonemal complex lateral elements and pairing the centromeres; however, genetic data show that are differences in the way Zip1 handles those processes (indicated by dark green and black respectively, see text). At the end of prophase I the synaptonemal complex disassembles; however, Zip1 is retained at the centromeres, where it mediates centromere pairing.

Figure 4. Centromere pairing in mouse

Both exchange and non-exchange chromosomes undergo centromere pairing in mouse spermatocytes. A) Chromosome spreads of mouse spermatocytes in late meiotic prophase I stained with antibodies against the central element of the synaptonemal complex SYCP1 and the lateral element SYCP3. The spread contains several desynapsed chromosome pairs in which the SYCP1 has largely disassembled, but with persisting blocks of SYCP1 at the centromeres (one end of the telocentric chromosome) and also at the chiasmata. B) Large images of an exchange and a non-exchange chromosome pair from the spread shown in panel A, with schematic diagrams. Figure 5. Model for centromere pairing and rotational freedom.

Figure 5. Model of centromere pairing and rotational freedom

A) Representation of bipolar kinetochore geometry of a homologous pair of chromosomes. Such geometry would promote the initial attachment of the kinetochores to microtubules coming from opposite poles (bipolar attachment). B) In absence of a link between the centromeres, the kinetochores may be able to rotate (represented by a twisted arrow). Kinetochores oriented to the same pole are represented. Such a configuration may increase the chances of attachment of both kinetochores to microtubules coming from the same spindle pole body (monopolar attachments) and consequent chromosome non-disjunction (not represented). C) Centromere pairing, by providing a link between the centromeres (black squares), will favor the formation of bipolar attachments by eliminating or reducing rotational freedom (red cross over twisted arrow) and inducing a bipolar kinetochore geometry. The centromere pairing may also provide or promote connections between the centromeres that provide tension when the centromeres become attached to microtubules from opposite poles, thereby stabilizing correct, bipolar, attachments. The presence of a crossover near the centromere might serve the same purposes (not represented).