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Abnormalities and Reduced Reproductive Potential of Sperm from Tnp1- and Tnp2-Null Double Mutant Mice¹

Department of Experimental Radiation Oncology,⁴ The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 Institute for Biogenesis Research,⁵ University of Hawaii Medical School, Honolulu, Hawaii 96822

Previous studies have demonstrated the importance of transition nuclear proteins, TP1 and TP2, in spermatogenesis and male fertility. However, importance of the overall level of transition proteins and their level of redundancy in the production of normal sperm is not clear. Epididymal sperm from the nine possible Tnp1 and Tnp2 null genotypes demonstrated a general decrease in normal morphology, motility, chromatin condensation, and degree of protamine 2 processing with decreasing levels of transition proteins in mutant sperm. Nuclei of some mutant epididymal sperm stained poorly with hematoxylin and DNA fluorochromes, suggesting that the DNA of these sperm underwent degradation during epididymal transport. When epididymal sperm were injected directly into oocytes, fertilization and embryonic development were reduced only in the two most severely affected genotypes. These phenotypes indicated some functional redundancy of transition proteins; however, redundancy of transition protein function was not complete, as, for example, sperm from double heterozygous males had fewer abnormalities than sperm from males homozygous for a single Tnp null mutation. Our study suggests that each TP fulfills some unique function during spermiogenesis even though sperm phenotypes strongly indicate defects are largely attributable to an overall gene dosage effect. Similarities between sperm defects found in Tnp mutants and infertile patients make the Tnp mutants a valuable tool with which to study outcomes following fertilization using sperm with compromised DNA integrity.

¹ Supported by funds from the NIH (grants HD-16843, HD-30284, and CA-16672), The Katherine and Harold Castle Foundation, and the Kosasa Family Foundation.

² Correspondence and current address: Cynthia R. Shirley, California National Primate Research Center, University of California, Davis, CA 95616. FAX: 530 752 2880; crshirley{at}primate.ucdavis.edu

³ Current address: Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima, 960-1295, Japan

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