Chromosome copies separate prematurely in oocytes from 8-week-old mice lacking OMC1, while women with two damaged copies of CCDC201, the proposed human counterpart of OMC1, reach menopause an average of 9 years earlier than other women
Chromosome copies separate prematurely in oocytes from 8-week-old mice lacking OMC1, while women with two damaged copies of CCDC201, the proposed human counterpart of OMC1, reach menopause an average of 9 years earlier than other women
On October 29, Nature Aging published a paper on an oocyte protein. Keiichiro Ishiguro (Chiba University), Tomoya Kitajima (RIKEN) and colleagues generated mice lacking the gene that encodes this protein.
Oocytes form during fetal development. Each begins meiosis and then pauses partway through, for months in mice and decades in women. The two copies of each chromosome (chromatids) are held together by cohesin rings containing the protein REC8. These rings assemble when DNA is replicated during fetal development, and no new rings form during the pause: experiments reported in 2016 found no renewal of these rings over several months in mice, leading the authors to conclude:
This implies that female fertility depends on the longevity of the cohesin proteins that established cohesion in the womb.
In old mice, oocyte chromosomes carry substantially less REC8, chromatids separate prematurely, and the oocyte ends up with an extra or missing chromosome. Ishiguro's group set out to find a protein that protects REC8 from this loss. They reasoned that it might be specific to oocytes, because male germ cells continually enter meiosis without a prolonged pause.
Among genes expressed in fetal oocytes but inactive in male germ cells, 219 showed altered activity in females with a mutation in STRA8, the protein that initiates meiosis. Oocytes in these females do not reach the pause, and the authors reasoned that genes supporting long-term oocyte survival might be less active in them. From these 219 genes, they selected the previously uncharacterized Ccdc201, which becomes active before the pause, and named it Omc1. They detected OMC1 protein only in oocytes, where it associates with chromosomes alongside REC8 and remains through oocyte maturation.
In mice lacking Omc1, REC8 associates normally with chromosomes in fetal oocytes, but substantially less remains on the chromosomes by 8 and 22 weeks. Total REC8 levels in oocytes from 8-week-old mice were unchanged, leading the authors to suggest that OMC1 retains REC8 already bound to chromosomes.
Females lacking Omc1 produced fewer offspring as they aged and almost none after 30 weeks. Over 40 weeks of mating, five of these females produced 112 offspring, compared with 231 from five females carrying one functional copy of the gene. In 8-week-old females lacking Omc1, individual chromatids had separated in roughly three-quarters of mature oocytes (compared with 8 % in normal females), and the number of separated chromatids per oocyte was comparable to that in normal 35-week-old females. Levels of the centromere protein CENP-A, whose depletion in aged oocytes compounds the damage caused by cohesin loss, remained unchanged in mice lacking Omc1, even as chromatid cohesion weakened.
The researchers injected mRNA encoding OMC1 into oocytes lacking Omc1 before maturation, and none of the 20 oocytes had separated chromatids. However, REC8 on chromosomes recovered only from 48 to 62 % of normal levels. The authors suggest that OMC1 supplied just before maturation counteracts the loss of cohesion during maturation, while defects accumulated during the pause persist. This would mean that OMC1 is needed during the pause itself.
CCDC201 is the proposed human counterpart of Omc1. In 2024, researchers at deCODE genetics studied age at menopause in 174 329 women. In 27 of them, both copies of CCDC201 carried a stop mutation that truncates the protein. These women reached menopause an average of 9 years earlier than the other women and had one fewer child. The authors of the new paper reproduced this mutation in the mouse protein and injected its mRNA into oocytes lacking Omc1: separated chromatids persisted in 17 of 18 oocytes, whereas mRNA encoding the normal protein eliminated them in all 18.