Mice lacking HSP90 beta fail to develop a placental labyrinth

The 90 kDa heat-shock proteins (HSP90s) play important roles during stress situations as general chaperones and under physiological conditions in the conformational activation of specific protein substrates, Vertebrates expre ss two cytosolic HSP90s (HSP90 alpha and HSP90 beta) ubiquitously, We have mutated the Hsp90 beta gene in murine embryonic stem cells and generated Hs p90 beta mutant mice, Heterozygous animals were phenotypically normal. Inte restingly, homozygous embryos developed normally until embryonic day 9.0/9. 5. Then, although Hsp90 beta is expressed ubiquitously, they exhibited phen otypic abnormalities restricted to the placenta. The mutant concepti failed to form a fetal placental labyrinth and died a day later. Fusion between t he allantois and the chorionic plate occurred, allantoic blood vessels inva ded the chorion, but then did not expand. Mutant trophoblast cells failed t o differentiate into trilaminar labyrinthine trophoblast. Despite conspicuo us similarities between HSP90 alpha and HSP90 beta at the molecular level, our data suggest that HSP90 beta has a key role in placenta development tha t cannot be performed by the endogenous HSP90 alpha alone. Analysis of chim eric concepti consisting of mutant embryos and tetraploid embryos or ES cel ls revealed that wild-type allantois was able to induce mutant trophoblast to differentiate. In contrast, trophoblast wild type at the Hsp90 beta locu s was unable to differentiate when in contact with mutant allantois, Theref ore, the primary defect caused by the Hsp90 beta mutation resided in the al lantois, The allantois mesoderm is thought to induce trophoblast differenti ation. Our results show that Hsp90 beta is a necessary component of this in duction process.