DIFFERENT TRANSMISSION RATES OF HERPESVIRUS THYMIDINE KINASE REPORTERTRANSGENES FROM FOUNDER MALE PARENTS AND MALE PARENTS OF SUBSEQUENT GENERATIONS

Previously we demonstrated that lines of transgenic mice carrying the herpes simplex type 1 virus thymidine kinase (HSV1-tk) reporter gene a re male-sterile. Ectopic transcription of the HSV1-tk reporter in the testis was initiated downstream of the normal translation initiation c odon and truncated proteins consistent with translational initiation a t the second and third ATG codons were synthesized. Here we describe t he effects on fertility 1) of converting the second and third ATG codo ns of the HSV1-tk reporter to CTG codons and 2) of utilizing the HSV t ype 2 thymidine kinase (HSV2-tk) reporter gene, in which the second AT G codon is located downstream of the ATP-binding pocket of the enzyme. Both reporters were coupled to the bovine thyroglobulin promoter (bTG -tk1 alpha and bTG-tk2 transgenes). The level of ectopic expression of these transgenes in the testis, relative to expression in the thyroid , was one to two orders of magnitude less than that of bTG-tk1. Sixty percent of male founders carrying the bTG-tk1 alpha and bTG-tk2 transg enes were fertile but did not transmit the transgene. In contrast, mos t males from subsequent generations were fertile and transmitted the t ransgenes at the expected frequency. This difference between founder m ales and male descendants is also observed with certain constructs in which the HSV1-tk reporter is coupled to other promoters. We attribute the effect to mosaicism among male founders, leading to competition b etween transgenic and nontransgenic spermatozoa and/or spermatogenic p recursor cells and resulting in a lack of fertilization by transgenic sperm that would successfully fertilize eggs in the absence of competi tion. (C) 1995 Wiley-Liss, Inc.