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The Hsp90 Cochaperone p23 Is Essential for Perinatal Survival

Iwona Grad,¹ Thomas A. McKee,² Sara M. Ludwig,³ Gary W. Hoyle,³ Patricia Ruiz,⁴ Wolfgang Wurst,⁵ Thomas Floss,⁵ Charles A. Miller III,^3, and Didier Picard^1,*

Département de Biologie Cellulaire, Université de Genève, Sciences III, 30 quai Ernest-Ansermet, 1211 Genève 4, Switzerland,¹ Service de Pathologie Clinique, Rue Micheli-du-Crest 24, 1211 Genève 4, Switzerland,² Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, Louisiana 70112,³ Max Planck Institute for Molecular Genetics, Department of Vertebrate Genomics, Center for Cardiovascular Research, Berlin, Germany,⁴ GSF National Research Center for Environment and Health, Institute of Developmental Genetics, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany⁵

Received 27 April 2006/ Returned for modification 1 June 2006/ Accepted 14 September 2006

The functions of molecular chaperones have been extensively investigated biochemically in vitro and genetically in bacteria and yeast. We have embarked on a functional genomic analysis of the Hsp90 chaperone machine in the mouse by disrupting the p23 gene using a gene trap approach. p23 is an Hsp90 cochaperone that is thought to stabilize Hsp90-substrate complexes and, independently, to act as the cytosolic prostaglandin E2 synthase. Gene deletions in budding and fission yeasts and knock-down experiments with the worm have not revealed any clear in vivo requirements for p23. We find that p23 is not essential for overall prenatal development and morphogenesis of the mouse, which parallels the observation that it is dispensable for proliferation in yeast. In contrast, p23 is absolutely necessary for perinatal survival. Apart from an incompletely formed skin barrier, the lungs of p23 null embryos display underdeveloped airspaces and substantially reduced expression of surfactant genes. Correlating with the known function of glucocorticoids in promoting lung maturation and the role of p23 in the assembly of a hormone-responsive glucocorticoid receptor-Hsp90 complex, p23 null fibroblast cells have a defective glucocorticoid response. Thus, p23 contributes a nonredundant, temporally restricted, and tissue-specific function during mouse development.

Published ahead of print on 25 September 2006.

These authors contributed equally.

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