A dominant-negative pleiotrophin mutant introduced by homologous recombination leads to germ-cell apoptosis in male mice

Pleiotrophin (PTN) is an 18-kDa heparin binding secretory growth/differenti ation factor for different cell types. Its gene is differentially expressed in both mesenchyme and central nervous system during development and highl y expressed in a number of different human tumors. Recently, a PTN mutant w as found to act as a dominant-negative effector of PTN signaling. We have n ow used homologous recombination to introduce the dominant-negative PTN mut ant into embryonic stem cells to generate chimeric mice. All highly chimeri c male mice with germinal epithelium exclusively derived from embryonic ste m cells with the heterologous PTN mutation were sterile. Their testes were uniformly atrophic, and the spermatocytes were strikingly apoptotic at all stages of development. The results support a central role of PTN signaling in normal spermatogenesis and suggest that interruption of PTN signaling ma y lead to sterility in males.