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Transgene Insertion Induced Dominant Male Sterility and Rescue of Male Fertility Using Round Spermatid Injection¹

^a Developmental Biology Program, Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland ^b The Institute of Biogenesis Research, Department of Anatomy and Reproductive Biology, University of Hawaii Medical School, Honolulu, Hawaii 96822 ^c Department of Comparative Medicine ^d Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon 97201-3098

Transgene insertions in the mouse often cause mutations at chromosomal loci. Analysis of insertion mutations that cause male sterility may lead to the identification of novel molecular mechanisms implicated in male fertility. Here we show a line of transgenic mice with dominant inheritance of male sterility (DMS) that was found amid several lines that were normally fertile. Transgene-positive males from this line invariably were sterile, whereas transgenic females and transgene-negative male littermates were fertile. Histologic analysis and TUNEL staining for apoptotic cells in DMS testis showed spermatogenesis arrest at metaphase of meiosis I (M-I), accompanied by massive apoptosis of spermatocytes. Meiosis I arrest was incomplete, however, as small numbers of spermatids and spermatozoa were found. Both round spermatids and spermatozoa were evaluated for their permissiveness in the assisted reproductive technologies intracytoplasmic sperm injection (ICSI) and round spermatid injection (ROSI). Surprisingly, ROSI but not ICSI gave live offspring, suggesting that mature sperm had deteriorated by the time of recovery from the epididymis. Mapping the transgene insertion by fluorescence in situ hybridization revealed a site on chromosome 14 D3-E1. Two candidate genes, GFR2 and GnRH, that were previously mapped to that region and the functions of which in spermatogenesis are well established were not altered in DMS. As a consequence, positional cloning of the DMS locus will be essential to identify new molecules potentially involved in arrest at M-I. Furthermore, mice carrying this genetic trait might be useful for studies of assisted reproductive technologies and male contraceptives.

First decision: 18 September 2001.

¹ This work was supported in part by the Oregon Cancer Institute.

² Correspondence: Manfred Baetscher, Department of Comparative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201-3098. FAX: 503 494 4338; baetsche{at}ohsu.edu

³ Current address: Department of Psychiatry & Behavioral Sciences, University of Washington Medical Center, Seattle, WA 98195

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