Transition nuclear proteins are required for normal chromatin condensation and functional sperm development

Abstract

The histone-to-protamine transition is important in the formation of spermatozoa. In mammals this involves two steps: replacement of histones by transition nuclear proteins (TPs) and replacement of TPs by protamines. To determine the functions of the TPs and their importance for sperm development, we generated mice lacking both TPs, since mice lacking only TP1 or TP2 were fertile. Our results indicated that TP1 and TP2 had partially complemented each other. In mice lacking both TPs, nuclear shaping, transcriptional repression, histone displacement, and protamine deposition proceeded relatively normally, but chromatin condensation was irregular in all spermatids, many late spermatids showed DNA breaks, and protamine 2 was not posttranslationally processed. Nevertheless, genomic integrity was maintained in mature spermatids, since efficient fertilization and production of offspring were achieved by intracytoplasmic sperm injection. However, many mature spermatids were retained in the testis, epididymal spermatozoa were drastically reduced in number and were highly abnormal, and the mice were sterile. Most epididymal spermatozoa were incapable of fertilization even using intracytoplasmic sperm injection. Thus, in mammals TPs are required for normal chromatin condensation, for reducing the number of DNA breaks, and for preventing the formation of secondary defects in spermatozoa, eventual loss of genomic integrity, and sterility.

Impact of a mild scrotal heat stress on DNA integrity in murine spermatozoa

“…have reported that during the normal process of spermiogenesis strand breaks are introduced in step 9 -11 spermatids and that these are associated with the condensation of the germ cell DNA and replacement of histones by protamines, but that after stage 11 all DNA breaks within the normal spermatid have been repaired and the histones have been completely replaced by protamines. Zhao et al (2004) have shown that transition proteins (TP) involved in the histone to protamine transition are also required for normal chromatin condensation, for reducing the number of DNA breaks and preventing a loss of genetic integrity. In the mouse transition proteins are expressed in step 10 to step 14 spermatids and the onset of protamine expression has been detected in step 10 spermatids using immunohistochemistry.…”

Spermiogenesis and DNA Repair: A Possible Etiology of Human Infertility and Genetic Disorders

“…The role of TPs and their structural properties are not well understood, but they play an important role in the condensation of the spermatid nucleus, as mice with deletions of both major transition proteins, TP1 and TP2, are infertile Zhao et al 2004]. As demonstrated by Shirley and colleagues , the interplay between TPs and protamines is quite complex.…”

Propagation of an infertile hermaphrodite mouse lacking germ cells by using nuclear transfer and embryonic stem cell technology

“…Some mutant, transgenic, and gene-targeted males are infertile because of defective spermiogenesis. The infertility of such males has been overcome by injection of spermatids into normal oocytes (6)(7)(8)(9). However, if the gonads of animals of interest lack germ cells, cloning would be the only way to propagate such lines.…”