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The Initiation of Meiotic Sex Chromosome Inactivation Sequesters DNA Damage Signaling from Autosomes in Mouse
Hironori Abe1, Kris G Alavattam1, Yueh-Chiang Hu1
1Division of Reproductive Sciences, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Abstract:
Meiotic sex chromosome inactivation (MSCI) is an essential event in the mammalian male germline. MSCI is directed by a DNA damage response (DDR) pathway centered on the phosphorylation of histone variant H2AX at serine 139 (termed γH2AX). The failure to initiate MSCI is linked to complete meiotic arrest and elimination of germ cells; however, the mechanisms underlying this arrest and elimination remain unknown. To address this question, we established a new separation-of-function mouse model for H2ax that shows specific and complete defects in MSCI. The genetic change is a point mutation in which another H2AX amino acid residue important in the DDR, tyrosine 142 (Y142), is converted to alanine (H2ax-Y142A). In H2ax-Y142A meiosis, the establishment of DDR signals on the chromosome-wide domain of the sex chromosomes is impaired. The initiation of MSCI is required for stage progression, which enables crossover formation, suggesting that the establishment of MSCI permits the timely progression of male meiosis. Our results suggest that normal meiotic progression requires the removal of ATR-mediated DDR signaling from autosomes. We propose a novel biological function for MSCI: the initiation of MSCI sequesters DDR factors from autosomes to the sex chromosomes at the onset of the pachytene stage, and the subsequent formation of an isolated XY nuclear compartment-the XY body-sequesters DDR factors to permit meiotic progression from the mid-pachytene stage onward. VIDEO ABSTRACT.
Insights
Meiotic sex chromosome inactivation (MSCI) initiation requires H2AX tyrosine 142. This process sequesters DNA damage response factors to the sex chromosomes, enabling male meiosis progression.
Area of Science:
- Reproductive Biology
- Molecular Genetics
- Cell Biology
Background:
- Meiotic sex chromosome inactivation (MSCI) is crucial for mammalian male germ cell development.
- MSCI is regulated by a DNA damage response (DDR) pathway involving histone H2AX phosphorylation (γH2AX).
- Failure in MSCI initiation leads to meiotic arrest and germ cell elimination, with underlying mechanisms unclear.
Purpose of the Study:
- To investigate the mechanisms behind meiotic arrest and germ cell elimination due to MSCI failure.
- To establish a mouse model to study the specific role of H2AX in MSCI.
- To elucidate the function of MSCI in male meiotic progression.
Main Methods:
- Development of a novel separation-of-function mouse model with an H2ax point mutation (H2ax-Y142A).
- Analysis of DNA damage response signaling during meiosis in the H2ax-Y142A mutant.
- Assessment of MSCI initiation, crossover formation, and meiotic stage progression.
Main Results:
- The H2ax-Y142A mutation specifically impairs MSCI initiation and DDR signaling on sex chromosomes.
- MSCI initiation is essential for timely male meiotic progression and crossover formation.
- Normal male meiosis requires the removal of ATR-mediated DDR signaling from autosomes.
Conclusions:
- MSCI initiation is critical for male meiosis progression by facilitating the timely removal of DDR signaling from autosomes.
- MSCI sequesters DDR factors to the sex chromosomes, forming an XY body that permits progression from the pachytene stage.
- The H2AX Y142 residue is vital for MSCI initiation and subsequent male germ cell development.
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