THE C-ROS TYROSINE KINASE RECEPTOR CONTROLS REGIONALIZATION AND DIFFERENTIATION OF EPITHELIAL-CELLS IN THE EPIDIDYMIS

The c-ros gene was originally identified in mutant form as an oncogene . The proto-oncogene encodes a tyrosine kinase receptor that is expres sed in a small number of epithelial cell types, including those of the epididymis. Targeted mutations of c-ros in the mouse reveal an essent ial role of the gene in male fertility. Male c-ros -/- animals do not reproduce, whereas the fertility of female animals is not affected. We demonstrate that c-ros is not required in a cell autonomous manner fo r male germ cell development or function. The gene, therefore, does no t affect sperm generation or function in a direct manner. The primary defect in the mutant animals was located in the epididymis, showing th at c-ros controls appropriate development of the epithelia, particular ly regionalization and terminal differentiation. The epididymal defect does not interfere with production or storage of sperm but, rather, w ith sperm maturation and the ability of sperm to fertilize in vivo. In terestingly, sperm isolated from c-ros -/- animals can fertilize in vi tro. Our results highlight the essential role of the epididymis in mal e fertility and demonstrate a highly specific function of the c-ros re ceptor tyrosine kinase during development of distinct epithelial cells .