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

PLoS Genet. 2006 Apr;2(4):e58. doi: 10.1371/journal.pgen.0020058. Epub 2006 Apr 21.

Abstract

ATRX is an X-encoded member of the SNF2 family of ATPase/helicase proteins thought to regulate gene expression by modifying chromatin at target loci. Mutations in ATRX provided the first example of a human genetic disease associated with defects in such proteins. To better understand the role of ATRX in development and the associated abnormalities in the ATR-X (alpha thalassemia mental retardation, X-linked) syndrome, we conditionally inactivated the homolog in mice, Atrx, at the 8- to 16-cell stage of development. The protein, Atrx, was ubiquitously expressed, and male embryos null for Atrx implanted and gastrulated normally but did not survive beyond 9.5 days postcoitus due to a defect in formation of the extraembryonic trophoblast, one of the first terminally differentiated lineages in the developing embryo. Carrier female mice that inherit a maternal null allele should be affected, since the paternal X chromosome is normally inactivated in extraembryonic tissues. Surprisingly, however, some carrier females established a normal placenta and appeared to escape the usual pattern of imprinted X-inactivation in these tissues. Together these findings demonstrate an unexpected, specific, and essential role for Atrx in the development of the murine trophoblast and present an example of escape from imprinted X chromosome inactivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cell Lineage
  • DNA Helicases / genetics*
  • DNA Helicases / physiology*
  • DNA Methylation
  • Dosage Compensation, Genetic
  • Female
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Models, Genetic
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / physiology*
  • Trophoblasts / metabolism
  • X Chromosome Inactivation*
  • X-linked Nuclear Protein

Substances

  • Nuclear Proteins
  • DNA Helicases
  • Atrx protein, mouse
  • X-linked Nuclear Protein