Meikin is a conserved regulator of meiosis-I-specific kinetochore function. Kim J et al. (2015) The kinetochore is the crucial apparatus regulating chromosome segregation in mitosis and meiosis. Particularly in meiosis I, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation) and centromeric cohesion mediated by cohesin is protected in the following anaphase. Although meiotic kinetochore factors have been identified only in budding and fission yeasts, these molecules and their functions are thought to have diverged earlier. Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive. Here we have identified in mouse a meiosis-specific kinetochore factor that we termed MEIKIN, which functions in meiosis I but not in meiosis II or mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin. These functions are mediated mainly by the activity of Polo-like kinase PLK1, which is enriched to kinetochores in a MEIKIN-dependent manner. Our integrative analysis indicates that the long-awaited key regulator of meiotic kinetochore function is Meikin, which is conserved from yeasts to humans.//////////////////
NCBI Summary:
The protein encoded by this gene is a member of the shugoshin family of proteins. This protein is thought to protect centromeric cohesin from cleavage during mitotic prophase by preventing phosphorylation of a cohesin subunit. Reduced expression of this gene leads to the premature loss of centromeric cohesion, mis-segregation of sister chromatids, and mitotic arrest. Evidence suggests that this protein also protects a small subset of cohesin found along the length of the chromosome arms during mitotic prophase. An isoform lacking exon 6 has been shown to play a role in the cohesion of centrioles (PMID: 16582621 and PMID:18331714). Mutations in this gene have been associated with Chronic Atrial and Intestinal Dysrhythmia (CAID) syndrome, characterized by the co-occurrence of Sick Sinus Syndrome (SSS) and Chronic Intestinal Pseudo-obstruction (CIPO) within the first four decades of life (PMID:25282101). Fibroblast cells from CAID patients exhibited both increased cell proliferation and higher rates of senescence. Pseudogenes of this gene have been found on chromosomes 1 and 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]
General function
Comment
Age-related increase in aneuploidy and alteration of gene expression in mouse first polar bodies. Jiao ZX 2014 et al.
PURPOSE
To confirm that aneuploidy candidate genes are detectable in the first polar body (PB1) of MII oocytes and to investigate the age-dependent molecular changes in PB1.
METHODS
Aged (12-to 15-mo-old) and young (2-mo-old) mice were administered pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotrophin (hCG). MII oocytes were obtained and the first PB was removed. mRNA from each PB and its sibling oocyte was reverse transcribed. Real-time PCR was performed to quantify the expression of six genes (BUB1, CDC20, Filia, MCAK, SGOL1, SMC1A) in single PB.
RESULTS
We first demonstrated that detection and quantification of transcripts associated with aneuploidy in single mouse oocyte and sibling PB1 is possible and the relative abundance of mRNA transcripts in a single PB faithfully reflects the relative abundance of that transcript in its sibling oocyte. We further found that transcript levels were significantly lower in aged PBs compared with young PBs (P<0.05).
CONCLUSIONS
Our results suggest that the detection and analysis of polar body mRNA may provide insight in age-related aneuploidy in oocyte. This analysis is a novel concept to investigate the genesis of chromosome abnormality and could potentially assist in the characterization of mechanisms underlying key molecular origin of female meiotic aneuploidy, which would be of great scientific and clinical value.
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Cellular localization
Comment
Ovarian function
Early embryo development
Comment
Shugoshin1 may play important roles in separation of homologous chromosomes and sister chromatids during mouse oocyte meiosis.
PLoS ONE. 2008;3(10):e3516.
Shugoshin1 may play important roles in separation of homologous chromosomes and sister chromatids during mouse oocyte meiosis. Yin S et al. BACKGROUND: Homologous chromosomes separate in meiosis I and sister chromatids separate in meiosis II, generating haploid gametes. To address the question why sister chromatids do not separate in meiosis I, we explored the roles of Shogoshin1 (Sgo1) in chromosome separation during oocyte meiosis. METHODOLOGY/PRINCIPAL FINDINGS: Sgo1 function was evaluated by exogenous overexpression to enhance its roles and RNAi to suppress its roles during two meioses of mouse oocytes. Immunocytochemistry and chromosome spread were used to evaluate phenotypes. The exogenous Sgo1 overexpression kept homologous chromosomes and sister chromatids not to separate in meiosis I and meiosis II, respectively, while the Sgo1 RNAi promoted premature separation of sister chromatids. CONCLUSIONS: Our results reveal that prevention of premature separation of sister chromatids in meiosis I requires the retention of centromeric Sgo1, while normal separation of sister chromatids in meiosis II requires loss of centromeric Sgo1.
Expression regulated by
Comment
Ovarian localization
Oocyte
Comment
SGO1 Maintains Bovine Meiotic and Mitotic Centromeric Cohesions of Sister Chromatids and Directly Affects Embryo Development. Yin FX 2013 et al.
Shugoshin (SGO) is a critical factor that enforces cohesion from segregation of paired sister chromatids during mitosis and meiosis. It has been studied mainly in invertebrates. Knowledge of SGO(s) in a mammalian system has only been reported in the mouse and Hela cells. In this study, the functions of SGO1 in bovine oocytes during meiotic maturation, early embryonic development and somatic cell mitosis were investigated. The results showed that SGO1 was expressed from germinal vesicle (GV) to the metaphase II stage. SGO1 accumulated on condensed and scattered chromosomes from pre-metaphase I to metaphase II. The over-expression of SGO1 did not interfere with the process of homologous chromosome separation, although once separated they were unable to move to the opposing spindle poles. This often resulted in the formation of oocytes with 60 replicated chromosomes. Depletion of SGO1 in GV oocytes affected chromosomal separation resulting in abnormal chromosome alignment at a significantly higher proportion than in control oocytes. Knockdown of SGO1 expression significantly decreased the embryonic developmental rate and quality. To further confirm the function(s) of SGO1 during mitosis, bovine embryonic fibroblast cells were transfected with SGO1 siRNAs. SGO1 depletion induced the premature dissociation of chromosomal cohesion at the centromere and along the chromosome arm giving rise to abnormal appearing mitotic patterns. The results of this study infer that SGO1 is involved in the centromeric cohesion of sister chromatids and chromosomal movement towards the spindle poles. Depletion of SGO1 causes arrestment of cell division in meiosis and mitosis.
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Expression profiles of cohesins, shugoshins and spindle assembly checkpoint genes in rhesus macaque oocytes predict their susceptibility for aneuploidy during embryonic development. Dupont C et al. High frequencies of chromosomal anomalies are reported in human and non-human primate in vitro-produced preimplantation embryos. It is unclear why certain embryos develop aneuploidies while others remain euploid. A differential susceptibility to aneuploidy is most likely a consequence of events that occur before oocyte collection. One hypothesis is that the relative transcript levels of cohesins, shugoshins and spindle assembly checkpoint genes are correlated with the occurrence of chromosomal anomalies. Transcript levels of these genes were quantified in individual oocytes that were either mature (group 1, low aneuploidy rate) or immature (group 2, high aneuploidy rate) at retrieval, utilizing TaqMan-based real-time PCR. The transcript level in each oocyte was categorized as absent, below the median or above the median in order to conduct comparisons. Statistically significant differences were observed between group 1 and group 2 for SGOL1 and BUB1. There were more oocytes with SGOL1 expression levels above the median in group 1, while oocytes lacking BUB1 were only observed in group 1. These findings suggest that higher SGOL1 levels in group 1 oocytes could better protect against a premature separation of sister chromatids than in embryos derived from group 2 oocytes. The absence of BUB1 transcripts in group 1 was frequently associated with reduced expression of either mitotic cohesins or shugoshins. We hypothesize that ablation of BUB1 could induce mitotic arrest in oocytes that fail to express a complete complement of cohesins and shugoshins, thereby reducing the number of developing aneuploid preimplantation embryos.
Structure and function of the PP2A-shugoshin interaction. Xu Z et al. Accurate chromosome segregation during mitosis and meiosis depends on shugoshin proteins that prevent precocious dissociation of cohesin from centromeres. Shugoshins associate with PP2A, which is thought to dephosphorylate cohesin and thereby prevent cleavage by separase during meiosis I. A crystal structure of a complex between a fragment of human Sgo1 and an AB'C PP2A holoenzyme reveals that Sgo1 forms a homodimeric parallel coiled coil that docks simultaneously onto PP2A's C and B' subunits. Sgo1 homodimerization is a prerequisite for PP2A binding. While hSgo1 interacts only with the AB'C holoenzymes, its relative, Sgo2, interacts with all PP2A forms and may thus lead to dephosphorylation of distinct substrates. Mutant shugoshin proteins defective in the binding of PP2A cannot protect centromeric cohesin from separase during meiosis I or support the spindle assembly checkpoint in yeast. Finally, we provide evidence that PP2A's recruitment to chromosomes may be sufficient to protect cohesin from separase in mammalian oocytes.