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First published online 28 February 2007
doi: 10.1242/dev.000018

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Meiotic sex chromosome inactivation

Division of Stem Cell Biology and Developmental Genetics, MRC NIMR, The Ridgeway, Mill Hill, London NW7 1AA, UK.

View larger version (55K): [in this window] [in a new window]   Fig. 1. Overview of XY activity during spermatogenesis. Transcriptional activity of the X and Y chromosomes is shown, with green indicating high expression and orange indicating low expression. The X and Y chromosomes are transcriptionally active during type A, intermediate (In) and type B spermatogonial divisions. They remain active during leptotene and zygotene, although total nuclear transcription is low during this time. On entry into pachytene, BRCA1 and ATR coat the entire length of the unsynapsed regions of the X and Y axial elements, followed by the translocation of ATR to the surrounding chromatin, where H2AX phosphorylation and MSCI takes place. Following meiosis, X and Y chromosome repression is maintained and the X and Y chromosomes appear as heterochromatic domains called post-meiotic sex chromatin (PMSC). This is shown as the light-turquoise structure located next to the dark-turquoise chromocentre - the site at which centromeres cluster. Elong., elongated; sec., secondary.

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View larger version (49K): [in this window] [in a new window]   Fig. 2. Schematic representation of MSCI. (A) During leptotene, widespread ATM-dependent H2AX phosphorylation occurs in response to meiotic-DNA DSB formation. BRCA1 and ATR form foci on newly forming axial element (AEs). (B) During zygotene, synapsis coincides with the loss of BRCA1, ATR and H2AX from autosomal AEs. BRCA1, ATR and H2AX remain as foci on the AEs of autosomes that have not yet synapsed and on the AE of the X chromosome. (C) Zygotene-pachytene transition. Autosomal synapsis is complete and recombination-related H2AX disappears. BRCA1- and ATR-staining becomes linear on the X and Y AEs. Meiotic DNA is arranged in loops attached at their bases to the AEs. (D) Early pachytene. ATR translocates along DNA loops, where it phosphorylates H2AX, resulting in MSCI and in the formation of the sex body. (E) Mid-to-late pachytene. Other histone modifications [e.g. the production of H3K9me2, uH2A and histone variants (e.g. H2AFY)] ensure the maintenance of MSCI. (F) Diplotene-to-diakinesis. The X and Y chromosomes migrate to the centre of the nucleus. BRCA1, ATR and H2AX are lost from the X and Y chromosomes, but the other modifications remain. These modifications ensure the maintenance of MSCI throughout the meiotic divisions (G) and into spermatids (H), and is termed post-meiotic sex chromosome repression (PSCR).

View larger version (41K): [in this window] [in a new window]   Fig. 3. Meiotic sterility caused by MSUC and by MSCI failure. (A) In normal (XY) males, silencing of the single X chromosome by MSCI is tolerated because essential X-encoded genes have autosomally integrated retrogene copies that are expressed during the precise time-window of MSCI-to-PSCR. (B) When autosomes fail to synapse, they are also silenced by MSUC. If unsynapsed autosomal segments contain a gene or genes crucial for meiosis, those genes will be silenced, causing meiotic arrest. (C) Allowing either the X or Y chromosome to synapse, as seen in XYY males, allows MSCI escape, with the ensuing expression of sex-linked genes causing meiotic arrest. (D) In XX females, all chromosomes have homologues and are thus completely synapsed. (E) In the XO female mouse, the single X chromosome has no synaptic partner and is therefore silenced by MSUC. Because no autosomal retrogenes are activated in the female gonad, these XO oocytes perish. (F) In approximately one-third of XO oocytes, the single X chromosome circumvents MSUC by synapsing non-homologously either with itself, to form a hairpin, or with other chromosomes.