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Molecular and Cellular Biology, November 2001, p. 7243-7255, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7243-7255.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Targeted Disruption of the Transition Protein 2 Gene Affects Sperm Chromatin Structure and Reduces Fertility in Mice†

Ming Zhao,1,* Cynthia R. Shirley,1 Y. Eugene Yu,1,Dagger Bhagyalaxmi Mohapatra,1,§ Yun Zhang,1,|| Emmanual Unni,1,# Jian M. Deng,2 Nelson A. Arango,2 Nicholas H. A. Terry,1 Michael M. Weil,1 Lonnie D. Russell,3,dagger dagger Richard R. Behringer,2 and Marvin L. Meistrich1

Departments of Experimental Radiation Oncology1 and Molecular Genetics,2 University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois 629013

Received 24 April 2001/Returned for modification 5 July 2001/Accepted 31 July 2001

During mammalian spermiogenesis, major restructuring of chromatin takes place. In the mouse, the histones are replaced by the transition proteins, TP1 and TP2, which are in turn replaced by the protamines, P1 and P2. To investigate the role of TP2, we generated mice with a targeted deletion of its gene, Tnp2. Spermatogenesis in Tnp2 null mice was almost normal, with testis weights and epididymal sperm counts being unaffected. The only abnormality in testicular histology was a slight increase of sperm retention in stage IX to XI tubules. Epididymal sperm from Tnp2-null mice showed an increase in abnormal tail, but not head, morphology. The mice were fertile but produced small litters. In step 12 to 16 spermatid nuclei from Tnp2-null mice, there was normal displacement of histones, a compensatory translationally regulated increase in TP1 levels, and elevated levels of precursor and partially processed forms of P2. Electron microscopy revealed abnormal focal condensations of chromatin in step 11 to 13 spermatids and progressive chromatin condensation in later spermatids, but condensation was still incomplete in epididymal sperm. Compared to that of the wild type, the sperm chromatin of these mutants was more accessible to intercalating dyes and more susceptible to acid denaturation, which is believed to indicate DNA strand breaks. We conclude that TP2 is not a critical factor for shaping of the sperm nucleus, histone displacement, initiation of chromatin condensation, binding of protamines to DNA, or fertility but that it is necessary for maintaining the normal processing of P2 and, consequently, the completion of chromatin condensation.

* Corresponding author. Mailing address: Department of Experimental Radiation Oncology, Box 66, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 794-4858. Fax: (713) 794-5369. E-mail: mzhao{at}mdanderson.org.

dagger This paper is dedicated to the memory of Lonnie Russell and his many contributions to our understanding of spermatogenesis.

Dagger Present address: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.

§ Present address: Department of Pediatrics-Cardiology, Baylor College of Medicine, Houston, TX 77030.

|| Present address: Cancer Biology, Chemical Industry Institute of Toxicology, Centers for Health Research, Research Triangle Park, NC 27709.

# Present address: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.

dagger dagger Deceased 11 July 2001.

Molecular and Cellular Biology, November 2001, p. 7243-7255, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7243-7255.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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