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Comment |
Smc1β is required for activation of SAC during mouse oocyte meiosis. Miao Y et al. (2017) Smc1β is a meiosis-specific cohesin subunit that is essential for sister chromatid cohesion and DNA recombination. Previous studies have shown that Smc1β-deficient mice in both sexes are sterile. Ablation of Smc1β during male meiosis leads to the blockage of spermatogenesis in pachytene stage, and ablation of Smc1β during female meiosis generates a highly error-prone oocyte although it could develop to metaphase II stage. However, the underlying mechanisms regarding how Smc1β maintains the correct meiotic progression in mouse oocytes have not been clearly defined. Here, we find that GFP-fused Smc1β is expressed and localized to the chromosomes from GV to MII stages during mouse oocyte meiotic maturation. Knockdown of Smc1β by microinjection of gene-specific morpholino causes impaired the spindle apparatus and chromosome alignment which are highly correlated with the defective kinetochore-microtubule attachments, consequently resulting in a prominently higher incidence of aneuploid eggs. In addition, the premature extrusion of polar bodies and escape of metaphase I arrest induced by low dose of nocodazole treatment in Smc1β-depleted oocytes indicates that Smc1β is essential for activation of spindle assembly checkpoint (SAC) activity. Collectively, we identify a novel function of Smc1β as a SAC participant beyond its role in chromosome cohesion during mouse oocyte meiosis.//////////////////
Age-Related Decrease of Meiotic Cohesins in Human Oocytes. Tsutsumi M 2014 et al.
Aneuploidy in fetal chromosomes is one of the causes of pregnancy loss and of congenital birth defects. It is known that the frequency of oocyte aneuploidy increases with the human maternal age. Recent data have highlighted the contribution of cohesin complexes in the correct segregation of meiotic chromosomes. In mammalian oocytes, cohesion is established during the fetal stages and meiosis-specific cohesin subunits are not replenished after birth, raising the possibility that the long meiotic arrest of oocytes facilitates a deterioration of cohesion that leads to age-related increases in aneuploidy. We here examined the cohesin levels in dictyate oocytes from different age groups of humans and mice by immunofluorescence analyses of ovarian sections. The meiosis-specific cohesin subunits, REC8 and SMC1B, were found to be decreased in women aged 40 and over compared with those aged around 20 years (P<0.01). Age-related decreases in meiotic cohesins were also evident in mice. Interestingly, SMC1A, the mitotic counterpart of SMC1B, was substantially detectable in human oocytes, but little expressed in mice. Further, the amount of mitotic cohesins of mice slightly increased with age. These results suggest that, mitotic and meiotic cohesins may operate in a coordinated way to maintain cohesions over a sustained period in humans and that age-related decreases in meiotic cohesin subunits impair sister chromatid cohesion leading to increased segregation errors.
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Aging predisposes oocytes to meiotic nondisjunction when the cohesin subunit SMC1 is reduced. Subramanian VV et al. In humans, meiotic chromosome segregation errors increase dramatically as women age, but the molecular defects responsible are largely unknown. Cohesion along the arms of meiotic sister chromatids provides an evolutionarily conserved mechanism to keep recombinant chromosomes associated until anaphase I. One attractive hypothesis to explain age-dependent nondisjunction (NDJ) is that loss of cohesion over time causes recombinant homologues to dissociate prematurely and segregate randomly during the first meiotic division. Using Drosophila as a model system, we have tested this hypothesis and observe a significant increase in meiosis I NDJ in experimentally aged Drosophila oocytes when the cohesin protein SMC1 is reduced. Our finding that missegregation of recombinant homologues increases with age supports the model that chiasmata are destabilized by gradual loss of cohesion over time. Moreover, the stage at which Drosophila oocytes are most vulnerable to age-related defects is analogous to that at which human oocytes remain arrested for decades. Our data provide the first demonstration in any organism that, when meiotic cohesion begins intact, the aging process can weaken it sufficiently and cause missegregation of recombinant chromosomes. One major advantage of these studies is that we have reduced but not eliminated the SMC1 subunit. Therefore, we have been able to investigate how aging affects normal meiotic cohesion. Our findings that recombinant chromosomes are at highest risk for loss of chiasmata during diplotene argue that human oocytes are most vulnerable to age-induced loss of meiotic cohesion at the stage at which they remain arrested for several years.
Accelerated Ovarian Aging in the Absence of the Transcription Regulator TAF4B in Mice. Lovasco LA et al. The mammalian ovary is unique in that its reproductive lifespan is limited by oocyte quantity and quality. Oocytes are recruited from a finite pool of primordial follicles that are usually exhausted from the ovary during mid-adult life. If regulation of this pool is perturbed, the reproductive capacity of the ovary is compromised. TAF4B is a gonadal-enriched subunit of the TFIID complex required for female fertility in mice. Previous characterization of TAF4B-deficient ovaries revealed several reproductive deficits that collectively result in infertility. However, the etiology of such fertility defects remains unknown. By assaying estrous cycle, ovarian pathology and gene expression changes in young Taf4b-null female mice, we show that TAF4B-deficient females exhibit premature reproductive senescence. The rapid decline of ovarian function in Taf4b-null mice begins in early postnatal life and follicle depletion is completed by sixteen weeks. To uncover differences in gene expression that may underlie accelerated ovarian aging, we compared genome-wide expression profiles of three week old, pre-pubescent Taf4b-null and wildtype ovaries. At three weeks of age, decreased gene expression in Taf4b-null ovaries is similar to those seen in aged ovaries revealing several molecular signatures of premature reproductive senescence, including reduced Smc1b. One significantly reduced transcript in the young TAF4B-null ovary codes for MOV10L1, a putative germline-specific RNA helicase that is related to the Drosophila RNA interference protein armitage. We show here that Mov10l1 is expressed in mouse oocytes and that its expression is sensitive to TAF4B level, linking TAF4B to the post-transcriptional control of ovarian gene expression.
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Mutations |
4 mutations
Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: A spontaneous Smc1b mutation causes cohesin protein dysfunction and sterility in mice. Takabayashi S et al. In this paper, we describe a novel spontaneous mutation of the Smc1b gene coding a cohesin component, which causes female and male sterility.We have discovered an ICR male mouse with a novel autosomal recessive gene that causes small gonads and sterility in both sexes. Mutant female and male mice homozygous for the novel sterility gene had normal body weights and showed normal mating behavior, but did not produce any offspring. Histological examination showed that Sertoli cells and spermatogonia were present in the testicular seminiferous tubules in 8-week-old mutant male mice, but no spermatids or spermatozoa were observed. Mutant females showed a markedly reduced number of oocytes with age. The novel sterility gene mapped between D15Mit105 (47.9cM) and D15Mit171 (54.5cM) on chromosome 15. Sequences of three candidate sterility genes, Dmc1, Mei1 and Smc1b, which are closely linked to these microsatellite markers, were compared between normal and mutant mice. The Dmc1 and Mei1 genes showed the same sequences in both normal and mutant mice, but the Smc1b gene had a deletion of 16 nucleotides in exon 5, in the mutant mice. We concluded that this deletion led to a frame-shift, which generated a stop codon at position 761 (amino acid 247) of the Smc1b cDNA in mutant mice.
Species: mouse
Mutation name: None
type: null mutation
fertility: fertile
Comment: Oocyte cohesin expression restricted to predictyate stages provides full fertility and prevents aneuploidy. Revenkova E et al. To ensure correct meiotic chromosome segregation, sister chromatid cohesion (SCC) needs to be maintained from its establishment in prophase I oocytes before birth until continuation of meiosis into metaphase II upon oocyte maturation in the adult. Aging human oocytes suffer a steep increase in chromosome missegregation and aneuploidy, which may be caused by loss of SCC through slow deterioration of cohesin [1-3]. This hypothesis assumes that cohesin expression in embryonic oocytes is sufficient to provide adequate long-term SCC. With increasing age, mouse oocytes deficient in the meiosis-specific cohesin SMC1?massively lose SCC and chiasmata [3, 4]. To test the deterioration hypothesis, we specifically and highly efficiently inactivated the mouse Smc1?gene at the primordial follicle stage shortly after birth, when oocytes had just entered meiosis I dictyate arrest. In the adult, however, irrespective of oocyte age, chiasma positions and SCC are normal. Frequency and size of litters prove full fertility even in aged females. Thus, SMC1?cohesin needs only be expressed during prophase I prior to the primordial follicle stage to ensure SCC up to advanced age of mice.
Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Identification of Multiple Gene Mutations Accounts for a new Genetic Architecture of Primary Ovarian Insufficiency. Bouilly J et al. (2017) Idiopathic primary ovarian insufficiency (POI) is a major cause of amenorrhea and infertility. POI affects 1% of women before age 40 years, and several genetic causes have been reported. To date, POI has been considered a monogenic disorder. The aim of this study was to identify novel gene variations and to investigate if individuals with POI harbor mutation in multiple loci. One hundred well-phenotyped POI patients were systematically screened for variants in 19 known POI loci (and potential candidate genes) using next-generation sequencing. At least one rare protein-altering gene variant was identified in 19 patients, including missense mutations in new candidate genes, namely SMC1β and REC8 (involved in the cohesin complex) and LHX8, a gene encoding a transcription factor. Novel or recurrent deleterious mutations were also detected in the known POI candidate genes NOBOX, FOXL2, SOHLH1, FIGLA, GDF9, BMP15, and GALT. Seven patients harbor mutations in two loci, and this digenicity seems to influence the age of symptom onset. Genetic anomalies in women with POI are more frequent than previously believed. Digenic findings in several cases suggest that POI is not a purely monogenic disorder and points to a role of digenicity. The genotype-phenotype correlations in some kindreds suggest that a synergistic effect of several mutations may underlie the POI phenotype.//////////////////
Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: SMC1beta-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction Hodges CA, et al .
Mitotic chromosome segregation is facilitated by the cohesin complex, which maintains physical connections between sister chromatids until anaphase. Meiotic cell division is considerably more complex, as cohesion must be released sequentially to facilitate orderly segregation of chromosomes at both meiosis I and meiosis II. This necessitates meiosis-specific cohesin components; recent studies in rodents suggest that these influence chromosome behavior during both cell division and meiotic prophase. To elucidate the role of the meiosis-specific cohesin SMC1beta (encoded by Smc1l2) in oogenesis, we carried out meiotic studies of female SMC1beta-deficient mice. Our results provide the first direct evidence that SMC1beta acts as a chiasma binder in mammals, stabilizing sites of exchange until anaphase. Additionally, our observations support the hypothesis that deficient cohesion is an underlying cause of human age-related aneuploidy.
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