Dataset Information

Rejuvenation of meiotic cohesion in oocytes during prophase I is required for chiasma maintenance and accurate chromosome segregation.

ABSTRACT: Chromosome segregation errors in human oocytes are the leading cause of birth defects, and the risk of aneuploid pregnancy increases dramatically as women age. Accurate segregation demands that sister chromatid cohesion remain intact for decades in human oocytes, and gradual loss of the original cohesive linkages established in fetal oocytes is proposed to be a major cause of age-dependent segregation errors. Here we demonstrate that maintenance of meiotic cohesion in Drosophila oocytes during prophase I requires an active rejuvenation program, and provide mechanistic insight into the molecular events that underlie rejuvenation. Gal4/UAS inducible knockdown of the cohesion establishment factor Eco after meiotic S phase, but before oocyte maturation, causes premature loss of meiotic cohesion, resulting in destabilization of chiasmata and subsequent missegregation of recombinant homologs. Reduction of individual cohesin subunits or the cohesin loader Nipped B during prophase I leads to similar defects. These data indicate that loading of newly synthesized replacement cohesin rings by Nipped B and establishment of new cohesive linkages by the acetyltransferase Eco must occur during prophase I to maintain cohesion in oocytes. Moreover, we show that rejuvenation of meiotic cohesion does not depend on the programmed induction of meiotic double strand breaks that occurs during early prophase I, and is therefore mechanistically distinct from the DNA damage cohesion re-establishment pathway identified in G2 vegetative yeast cells. Our work provides the first evidence that new cohesive linkages are established in Drosophila oocytes after meiotic S phase, and that these are required for accurate chromosome segregation. If such a pathway also operates in human oocytes, meiotic cohesion defects may become pronounced in a woman's thirties, not because the original cohesive linkages finally give out, but because the rejuvenation program can no longer supply new cohesive linkages at the same rate at which they are lost.

SUBMITTER: Weng KA

PROVIDER: S-EPMC4161318 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Rejuvenation of meiotic cohesion in oocytes during prophase I is required for chiasma maintenance and accurate chromosome segregation.

Weng Katherine A KA Jeffreys Charlotte A CA Bickel Sharon E SE

PLoS genetics 20140911 9

Chromosome segregation errors in human oocytes are the leading cause of birth defects, and the risk of aneuploid pregnancy increases dramatically as women age. Accurate segregation demands that sister chromatid cohesion remain intact for decades in human oocytes, and gradual loss of the original cohesive linkages established in fetal oocytes is proposed to be a major cause of age-dependent segregation errors. Here we demonstrate that maintenance of meiotic cohesion in Drosophila oocytes during p ...[more]

PMID: 25211017

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Project description:The centromere is an epigenetic mark that is a loading site for the kinetochore during meiosis and mitosis. This mark is characterized by the H3 variant CENP-A, known as CID in Drosophila . In Drosophila , CENP-C is critical for maintaining CID at the centromeres and directly recruits outer kinetochore proteins after nuclear envelope break down. It is not known, however, if these two functions require the same CENP-C molecules. Furthermore, in Drosophila and many other metazoan oocytes, centromere maintenance and kinetochore assembly are separated by an extended prophase. Consistent with studies in mammals, CID is relatively stable and does not need to be expressed during prophase to remain at high levels in metaphase I of meiosis. Expression of CID during prophase can even be deleterious, causing ectopic localization to non-centromeric chromatin, abnormal meiosis and sterility. In contrast to CID, maintaining high levels of CENP-C requires expression during prophase. Confirming the importance of this loading, we found CENP-C prophase loading is required for multiple meiotic functions. In early meiotic prophase, CENP-C loading is required for sister centromere cohesion and centromere clustering. In late meiotic prophase, CENP-C loading is required to recruit kinetochore proteins. CENP-C is one of the few proteins identified in which expression during prophase is required for meiotic chromosome segregation. An implication of these results is that the failure to maintain recruitment of CENP-C during the extended prophase in oocytes would result in chromosome segregation errors in oocytes.Author summaryMeiosis in oocytes of diverse organisms, including humans and Drosophila, is characterized by a long prophase pause and a cell cycle arrest in meiosis I or meiosis II. These pauses could be a challenge for centromeres, whose components are replenished during G1, and then must remain with the chromosomes until the meiotic divisions. We have investigated the stability, prophase dynamics and function of centromere protein CENP-C. We show that CENP-C expression and loading onto centromeres during prophase is required for multiple meiotic functions. In contrast, the expression of other centromere partners CID/CENP-A and CAL1 is not required during meiotic prophase. Furthermore, expression of CID during prophase can be deleterious and result in ectopic kinetochore formation. CENP-C loading in prophase is required for sister centromere cohesion and kinetochore assembly. Our results provide the first description of CENP-C dynamics during meiosis and show that prophase expression is required for oocyte spindle assembly and function. CENP-C is among a small number of proteins that are required for the meiotic divisions but are loaded prior to prometaphase. Failure to maintain these proteins during the long prophase of oocyte meiosis may contribute to the increased aneuploidy associated with advanced maternal age.

Dataset Information

Rejuvenation of meiotic cohesion in oocytes during prophase I is required for chiasma maintenance and accurate chromosome segregation.

Publications

Rejuvenation of meiotic cohesion in oocytes during prophase I is required for chiasma maintenance and accurate chromosome segregation.

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