Loss of Atrx Affects Trophoblast Development and the Pattern of X-Inactivation in Extraembryonic Tissues

MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
PLoS Genetics (Impact Factor: 8.17). 05/2006; 2(4):e58. DOI: 10.1371/journal.pgen.0020058
Source: PubMed

ATRX belongs to a class of proteins that may modify how DNA is packaged into chromatin, altering the accessibility of other proteins in the nucleus to DNA. In this way, ATRX is thought to influence gene expression. Mutations in the ATRX gene, which is located on the female sex chromosome (X), provided the first example of a human disease (ATR-X syndrome) associated with defects in such proteins. Affected males (XMUTY) have multiple developmental abnormalities in a wide variety of systems. Currently, it is not understood how proteins like ATRX influence cell biology. To address this question, the authors deleted the version of the gene in mice, Atrx. Although affected male mice (XMUTY) started to develop normally, they died early in development because they failed to form a normal placenta. In the placenta, female mice normally inactivate the X chromosome that they inherit from their fathers (Xp), so if females inherit from their mother an X chromosome (Xm) that bears the abnormal copy of Atrx (XmMUTXp), one would predict that, like affected males, they would fail to form a normal placenta. The authors unexpectedly found this not to be so. They showed, instead, that in such females the normal, paternally derived Atrx gene is active. This study has therefore demonstrated an important facet of X-chromosome imprinting.

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Available from: Lorraine Rose, Mar 20, 2014
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    • "To assess this, female SV129 mice carrying a floxed allele of the X chromosome-linked ATRX gene (Garrick et al., 2006) were crossed with castaneus males to generate a male (SV129 3 Cast) F1 ESC line, which would allow allelic discrimination . The SV129 3 Cast ATRX Flox ESCs were transduced with an adenoviral Cre-GFP cassette (AdCre) to generate ATRX KO cells. "
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    • "It is known to indirectly regulate the G 2 /M transition [Fedele et al. 2001] and is also involved in apoptosis, DNA binding, transcription regulation of genes, and 3' mRNA processing and chromatin remodeling [Adair et al. 2007; Farnet and Bushman 1997; Herdegen and Leah 1998; Seth et al. 2006], which are key events in progression through oocyte meiotic maturation [Masui and Clarke 1979]. An interesting candidate gene associated with decreased competence is Atrx, which is involved in chromatin binding and DNA repair [Garrick et al. 2006; Picketts et al. 1998]. Of the 10 genes whose downregulation was associated with decreased competence four were growth factors, their receptors or regulators i.e., a decrease in insulin-like growth factor binding protein 3, the secreted signalling protein Bmp4, its receptor TGF beta receptor III (Tgfbr3), and a soluble Wnt receptor the secreted frizzled related I (Sfpr1). "
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    • "A conditional floxed allele of Atrx was engineered to allow early inactivation at the morula stage using the GATA-cre line of mice (Garrick et al. 2006). Newborn ATRX-null mice could not be recovered, and it was determined that the embryos died at or before E9.5, in part due to the failure to form a normal trophectoderm (Garrick et al. 2006). The lethality of ATRX-null embryos precludes loss-offunction studies in tissues such as the brain. "
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