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Elimination of Male Germ Cells in Transgenic Mice by the Diphtheria Toxin A Chain Gene Directed by the Histone H1t Promoter¹

^a Department of Chemistry & Biochemistry and ^b Department of Biological Sciences, University of South Carolina, Columbia, South Carolina 29208

ABSTRACT

Expression of the diphtheria toxin A-chain gene was directed to the male germ line by fusion to 1 kilobase of the 5'-flanking DNA of the rat histone H1t gene. Two independent lines of mice were established that expressed the toxic transgene. Female carriers were fertile; males were sterile although otherwise apparently normal. Adult transgenic males had very small testes that were virtually devoid of germ cells. A developmental study showed that germ cells survived until late fetal life but that testes of 3-day-old transgenic mice were severely depleted of prospermatogonia. During postnatal development of transgenic animals, remaining germ cells progressed to the pachytene stage of meiosis in 10% to 30% of tubular cross sections but degenerated before the completion of meiosis. By 3 mo of age the residual germ cells had almost completely disappeared. These transgenic lines demonstrate the complete tissue specificity of the H1t promoter and reveal a period of its activity just prior to formation of the definitive adult spermatogonial stem cell population. Whereas full expression of H1t occurs only in mid to late pachytene spermatocytes, one or more of the factors that impart tissue specificity to its expression must be transiently activated in the neonatal germ line. This report discusses the possibility that this genetic technique for eliminating germ cells may have practical application in making recipients for spermatogonial stem cell transplantation.

FOOTNOTES

First decision: 5 August 1999.

¹ This work was supported by NIH Grant HD-10793 and by a grant from the Venture Fund of the University of South Carolina.

² Correspondence: W.S. Kistler, Department of Chemistry and Biochemistry, University of South Carolina, 730 S. Main St., Columbia, SC 29208. FAX: 803 777 9521; kistler{at}psc.sc.edu

³ Current address: MIDI Labs, Inc., Newark, DE 19713.

⁴ Current address: Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110.

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