XIST-DEFICIENT MICE ARE DEFECTIVE IN DOSAGE COMPENSATION BUT NOT SPERMATOGENESIS

The X-linked Xist gene encodes a large untranslated RNA that has been implicated in mammalian dosage compensation and in spermatogenesis. To investigate the function of the Xist gene product, we have generated male and female mice that carry a deletion in the structural gene but maintain a functional Xist promoter. Mutant males were healthy and fer tile. Females that inherited the mutation from their mothers were also normal and had the wild-type paternal X chromosome inactive in every cell. In contrast to maternal transmission, females that carry the mut ation on the paternal X chromosome were severely growth-retarded and d ied early in embryogenesis. The wild-type maternal X chromosome was in active in every cell of the growth-retarded embryo proper, whereas bot h X chromosomes were expressed in the mutant female trophoblast where X inactivation is imprinted. However, an XO mouse with a paternally in herited Xist mutation was healthy and appeared normal. The imprinted l ethal phenotype of the mutant females is therefore due to the inabilit y of extraembryonic tissue with two active X chromosomes to sustain th e embryo. Our results indicate that the Xist RNA is required for femal e dosage compensation but plays no role in spermatogenesis.