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Failure of homologous synapsis and sex-specific reproduction problems.

Kurahashi H, Kogo H, Tsutsumi M, Inagaki H, Ohye T - Front Genet (2012)

Bottom Line: Recent advances in genetic manipulation technologies have increased our knowledge about the pachytene checkpoint and surveillance systems that detect chromosomal synapsis.This review focuses on the consequences of synapsis failure in humans and provides an overview of the mechanisms involved.We also discuss the sexual dimorphism of the involved pathways that leads to the differences in reproductive outcomes between males and females.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan.

ABSTRACT
The prophase of meiosis I ensures the correct segregation of chromosomes to each daughter cell. This includes the pairing, synapsis, and recombination of homologous chromosomes. A subset of chromosomal abnormalities, including translocation and inversion, disturbs these processes, resulting in the failure to complete synapsis. This activates the meiotic pachytene checkpoint, and the gametes are fated to undergo cell cycle arrest and subsequent apoptosis. Spermatogenic cells appear to be more vulnerable to the pachytene checkpoint, and male carriers of chromosomal abnormalities are more susceptible to infertility. In contrast, oocytes tend to bypass the checkpoint and instead generate other problems, such as chromosome imbalance that often leads to recurrent pregnancy loss in female carriers. Recent advances in genetic manipulation technologies have increased our knowledge about the pachytene checkpoint and surveillance systems that detect chromosomal synapsis. This review focuses on the consequences of synapsis failure in humans and provides an overview of the mechanisms involved. We also discuss the sexual dimorphism of the involved pathways that leads to the differences in reproductive outcomes between males and females.

No MeSH data available.


Related in: MedlinePlus

Hormad1 deficiency abrogates massive apoptosis in Spo11 deficiency. (A) Representative image of a uterus. Hormad1-deficient females carry only a small number of implantation sites (right) compared with the control (left). The lower panel shows a representative image of a conceptus from a Hormad1-deficient female with a non-developing fetus (right). (B) Representative data of the first meiotic metaphase (MI) of wild-type (WT) and Hormad1-deficient oocytes with only a small number of bivalents (right). The lower panel shows a representative photograph of the second meiotic metaphase (MII) of Hormad1-deficient oocytes with some monovalents (right). (C) Hematoxylin and eosin staining of ovary sections from 20-day-old female mice. The ovaries from Spo11-deficient mice are small with only a small number of follicles, while Spo11/Hormad1 double-knockout mice demonstrate the same size and oocyte number as the wild-type levels. (D) The number of oocytes in 20-day-old mice ovaries. The c-Kit positive oocytes are almost absent in the Spo11-deficient ovary, but are abundant in the Spo11/Hormad1 double-knockout ovaries (*P <0.05).
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Figure 3: Hormad1 deficiency abrogates massive apoptosis in Spo11 deficiency. (A) Representative image of a uterus. Hormad1-deficient females carry only a small number of implantation sites (right) compared with the control (left). The lower panel shows a representative image of a conceptus from a Hormad1-deficient female with a non-developing fetus (right). (B) Representative data of the first meiotic metaphase (MI) of wild-type (WT) and Hormad1-deficient oocytes with only a small number of bivalents (right). The lower panel shows a representative photograph of the second meiotic metaphase (MII) of Hormad1-deficient oocytes with some monovalents (right). (C) Hematoxylin and eosin staining of ovary sections from 20-day-old female mice. The ovaries from Spo11-deficient mice are small with only a small number of follicles, while Spo11/Hormad1 double-knockout mice demonstrate the same size and oocyte number as the wild-type levels. (D) The number of oocytes in 20-day-old mice ovaries. The c-Kit positive oocytes are almost absent in the Spo11-deficient ovary, but are abundant in the Spo11/Hormad1 double-knockout ovaries (*P <0.05).

Mentions: To further investigate the mechanisms of the pachytene checkpoints at the molecular level, we searched for candidate genes that are essential to synapsis by examining the expression profiles of mouse genes expressed during the prophase of meiosis I (Kogo et al., 2010). Among the hundreds of candidate genes, we focused on Hormad1, the mammalian ortholog of yeast Hop1, by its potential function in the synapsis surveillance system. Hormad1 is a HORMA domain protein that is located on the SC in the unsynapsed region (Wojtasz et al., 2009; Fukuda et al., 2010). Recently, we and others have reported detailed analyses of Hormad1-deficient mice. Hormad1-deficient mice are infertile and demonstrate extensive failure of homologous pairing and synapsis in both males and females (Shin et al., 2010; Daniel et al., 2011; Kogo et al., 2012). In males, spermatogenesis arrests during the pachytene due to the severe synapsis failure, and all spermatogenic cells undergo stage IV apoptosis. Unexpectedly, Hormad1-deficient ovaries contain a normal number of oocytes, despite the extensive asynapsis, and consequently produce aneuploid oocytes that lead to subsequent fetal death in utero (Figures 3A,B). The failure to eliminate oocytes with extensive synapsis failure in the Hormad1-deficient ovary prompted the hypothesis that Hormad1 itself might be required for the mammalian pachytene checkpoint mechanism.


Failure of homologous synapsis and sex-specific reproduction problems.

Kurahashi H, Kogo H, Tsutsumi M, Inagaki H, Ohye T - Front Genet (2012)

Hormad1 deficiency abrogates massive apoptosis in Spo11 deficiency. (A) Representative image of a uterus. Hormad1-deficient females carry only a small number of implantation sites (right) compared with the control (left). The lower panel shows a representative image of a conceptus from a Hormad1-deficient female with a non-developing fetus (right). (B) Representative data of the first meiotic metaphase (MI) of wild-type (WT) and Hormad1-deficient oocytes with only a small number of bivalents (right). The lower panel shows a representative photograph of the second meiotic metaphase (MII) of Hormad1-deficient oocytes with some monovalents (right). (C) Hematoxylin and eosin staining of ovary sections from 20-day-old female mice. The ovaries from Spo11-deficient mice are small with only a small number of follicles, while Spo11/Hormad1 double-knockout mice demonstrate the same size and oocyte number as the wild-type levels. (D) The number of oocytes in 20-day-old mice ovaries. The c-Kit positive oocytes are almost absent in the Spo11-deficient ovary, but are abundant in the Spo11/Hormad1 double-knockout ovaries (*P <0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 3: Hormad1 deficiency abrogates massive apoptosis in Spo11 deficiency. (A) Representative image of a uterus. Hormad1-deficient females carry only a small number of implantation sites (right) compared with the control (left). The lower panel shows a representative image of a conceptus from a Hormad1-deficient female with a non-developing fetus (right). (B) Representative data of the first meiotic metaphase (MI) of wild-type (WT) and Hormad1-deficient oocytes with only a small number of bivalents (right). The lower panel shows a representative photograph of the second meiotic metaphase (MII) of Hormad1-deficient oocytes with some monovalents (right). (C) Hematoxylin and eosin staining of ovary sections from 20-day-old female mice. The ovaries from Spo11-deficient mice are small with only a small number of follicles, while Spo11/Hormad1 double-knockout mice demonstrate the same size and oocyte number as the wild-type levels. (D) The number of oocytes in 20-day-old mice ovaries. The c-Kit positive oocytes are almost absent in the Spo11-deficient ovary, but are abundant in the Spo11/Hormad1 double-knockout ovaries (*P <0.05).
Mentions: To further investigate the mechanisms of the pachytene checkpoints at the molecular level, we searched for candidate genes that are essential to synapsis by examining the expression profiles of mouse genes expressed during the prophase of meiosis I (Kogo et al., 2010). Among the hundreds of candidate genes, we focused on Hormad1, the mammalian ortholog of yeast Hop1, by its potential function in the synapsis surveillance system. Hormad1 is a HORMA domain protein that is located on the SC in the unsynapsed region (Wojtasz et al., 2009; Fukuda et al., 2010). Recently, we and others have reported detailed analyses of Hormad1-deficient mice. Hormad1-deficient mice are infertile and demonstrate extensive failure of homologous pairing and synapsis in both males and females (Shin et al., 2010; Daniel et al., 2011; Kogo et al., 2012). In males, spermatogenesis arrests during the pachytene due to the severe synapsis failure, and all spermatogenic cells undergo stage IV apoptosis. Unexpectedly, Hormad1-deficient ovaries contain a normal number of oocytes, despite the extensive asynapsis, and consequently produce aneuploid oocytes that lead to subsequent fetal death in utero (Figures 3A,B). The failure to eliminate oocytes with extensive synapsis failure in the Hormad1-deficient ovary prompted the hypothesis that Hormad1 itself might be required for the mammalian pachytene checkpoint mechanism.

Bottom Line: Recent advances in genetic manipulation technologies have increased our knowledge about the pachytene checkpoint and surveillance systems that detect chromosomal synapsis.This review focuses on the consequences of synapsis failure in humans and provides an overview of the mechanisms involved.We also discuss the sexual dimorphism of the involved pathways that leads to the differences in reproductive outcomes between males and females.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan.

ABSTRACT
The prophase of meiosis I ensures the correct segregation of chromosomes to each daughter cell. This includes the pairing, synapsis, and recombination of homologous chromosomes. A subset of chromosomal abnormalities, including translocation and inversion, disturbs these processes, resulting in the failure to complete synapsis. This activates the meiotic pachytene checkpoint, and the gametes are fated to undergo cell cycle arrest and subsequent apoptosis. Spermatogenic cells appear to be more vulnerable to the pachytene checkpoint, and male carriers of chromosomal abnormalities are more susceptible to infertility. In contrast, oocytes tend to bypass the checkpoint and instead generate other problems, such as chromosome imbalance that often leads to recurrent pregnancy loss in female carriers. Recent advances in genetic manipulation technologies have increased our knowledge about the pachytene checkpoint and surveillance systems that detect chromosomal synapsis. This review focuses on the consequences of synapsis failure in humans and provides an overview of the mechanisms involved. We also discuss the sexual dimorphism of the involved pathways that leads to the differences in reproductive outcomes between males and females.

No MeSH data available.


Related in: MedlinePlus