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Gene and Protein Expression in the Epididymis of Infertile c-ros Receptor Tyrosine Kinase-Deficient Mice¹

Institute of Reproductive Medicine of the University,⁴ D-48129 Münster, Germany Department of Cell Biology and Biochemistry,⁵ Texas Tech University Health Sciences Center, Lubbock, Texas 79430 Institute of Biological Chemistry,⁶ Academia Sinica, Taipei, Taiwan, Republic of China Center for Reproductive Biology Research,⁷ Vanderbilt Medical Center, Nashville, Tennessee Department of Biology,⁸ Blaise Pascal University, CNRS UMR 6547 GEEM, Reproduction and Development, 63177 Aubière Cedex, France

Transgenic male mice bearing inactive mutations of the receptor tyrosine kinase c-ros lack the initial segment of the epididymis and are infertile. Several techniques were applied to determine differences in gene expression in the epididymal caput of heterozygous fertile (HET) and infertile homozygous knockout (KO) males that may explain the infertility. Complementary DNA arrays, gene chips, Northern and Western blots, and immunohistochemistry indicated that some proteins were downregulated, including the initial segment/proximal caput-specific genes c-ros, cystatin-related epididymal-spermatogenic (CRES), and lipocalin mouse epididymal protein 17 (MEP17), whereas other caput-enriched genes (glutathione peroxidase 5, a disintegrin and metalloproteinase [ADAM7], bone morphogenetic proteins 7 and 8a, A-raf, CCAAT/enhancer binding protein ß, PEA3) were unchanged. Genes normally absent from the initial segment (-glutamyltranspeptidase, prostaglandin D₂ synthetase, alkaline phosphatase) were expressed in the undifferentiated proximal caput of the KO. More distally, lipocalin 2 (24p3), CRISP1 (formerly MEP7), PEBP (MEP9), and mE-RABP (MEP10) were unchanged in expression. Immunohistochemistry and Western blots confirmed the absence of CRES in epididymal tissue and fluid and the continued presence of CRES in spermatozoa of the KO mouse. The glutamate transporters EAAC1 (EAAT3) and EAAT5 were downregulated and upregulated, respectively. The genes of over 70 transporters, channels, and pores were detected in the caput epididymidis, but in the KO, only three were downregulated and six upregulated. The changes in these genes could affect sperm function by modifying the composition of epididymal fluid and explain the infertility of the KO males. These genes may be targets for a posttesticular contraceptive.

¹ This work was supported by the Rockefeller-Schering Research Foundations' Application of Molecular Pharmacology for Post-Testicular Activity [AMPPA] Network (A.W.), the Deutsche Forschungsgemeinschaft 197/3-1 for "The male gamete: production, maturation, function" (C.H.Y.), NIH HD33903 (G.A.C.), and NICH HD36900 (M.C.O.C.).

² Correspondence: T.G. Cooper, Institute of Reproductive Medicine of the University, Domagkstraße 11, D-48129 Münster, Germany. FAX: +49 251 8356093; cooper{at}uni-muenster.de

³ Current address: Schering AG, 13342 Berlin, Germany

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