ESX1 IS AN X-CHROMOSOME-IMPRINTED REGULATOR OF PLACENTAL DEVELOPMENT AND FETAL GROWTH

In marsupials and mice, the paternally derived X chromosome is prefere ntially inactivated in the placental tissues of female embryos(1-4). W e show here that the X-linked homeobox gene Esx1 (refs 5,6), whose exp ression is restricted to extraembryonic tissues, is a chromosomally im printed regulator of placental morphogenesis and trophoblast different iation. Heterozygous female mice that inherited a mutant Esx1 allele f rom their father developed normally. Heterozygous females that inherit ed the Esx1 mutation from their mother, however, were born 20% smaller than normal and are identical in phenotype to hemizygous mutant males and homozygous mutant females. Although Esx1 mutant embryos were init ially comparable in size with controls at 13.5 days post coitum (dpc), their placentas were significantly larger. Defects in the morphogenes is of the labyrinthine layer were observed as early as 11.5 dpc. Subse quently, vascularization abnormalities developed at the maternal-fetal interface, causing fetal growth retardation. These results identify E sx1 as the first essential X-chromosome-imprinted regulator of placent al development that influences fetal growth, and may aid our understan ding human placental insufficiency syndromes.