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Molecular and Cellular Biology, October 2004, p. 8642-8648, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8642-8648.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Targeted Deletion of the Epididymal Receptor HE6 Results in Fluid Dysregulation and Male Infertility

Ben Davies,1* Claudia Baumann,1 Christiane Kirchhoff,2 Richard Ivell,2 Reinhard Nubbemeyer,3 Ursula-Friederike Habenicht,3 Franz Theuring,1,{dagger} and Ulrich Gottwald3,{dagger}

Center for Cardiovascular Research-Institute for Pharmacology and Toxicology, Charité-University Medicine, Berlin,1 Schering AG, Berlin,3 Institute for Hormone and Fertility Research, Hamburg, Germany2

Received 7 April 2004/ Returned for modification 13 June 2004/ Accepted 2 July 2004

Human epididymal protein 6 (HE6; also known as GPR64) is an orphan member of the LNB-7TM (B2) subfamily of G-protein-coupled receptors. Family members are characterized by the dual presence of a secretin-like (type II) seven-transmembrane (7TM) domain and a long cell adhesion-like extracellular domain. HE6 is specifically expressed within the efferent ductules and the initial segment of the epididymis, ductal systems involved in spermatozoon maturation. Here, we report that targeted deletion of the 7TM domain of the murine HE6 gene results in male infertility. Mutant mice reveal a dysregulation of fluid reabsorbtion within the efferent ductules, leading to a backup of fluid accumulation in the testis and a subsequent stasis of spermatozoa within the efferent ducts. The fertility phenotype of HE6 knockout mice identifies this receptor as a potential nonsteroidal, nontesticular target for future male contraceptives and identifies an in vivo function for a member of this unusual gene family.

* Corresponding author. Present address: Murinus GmbH, Falkenried 88, 20251 Hamburg, Germany. Phone: 49 40 42803 1660. Fax: 49 40 42803 1699. E-mail: b.davies{at}murinus.com.

{dagger} F.T. and U.G. contributed equally to this work.

Molecular and Cellular Biology, October 2004, p. 8642-8648, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8642-8648.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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