Testicular wild-type p53 expression in transgenic mice induces spermiogenesis alterations ranging from differentiation defects to apoptosis

Abstract

While p53 is dispensable for development, an excess of p53 has dramatic consequences on the embryogenesis and on the cell dierentiation. In an attempt to analyse in vivo the eects of p53 activity, we have generated transgenic mice expressing the wild-type p53 under the control of the metallothionein I promoter. In the three transgenic lines established, exogenous p53 is expressed constitutively in the postmeiotic cells of transgenic males and two lines are subfertile. Transgenic males expressing the upper level of p53 produce few spermatozoa since the majority of developing spermatids undergo apoptosis. In the subfertile males exhibiting an intermediate amount of p53, teratozoospermia is obvious suggesting an altered terminal dierentiation of postmeiotic cells. In contrast lower level of p53 does not lead the third line to sterility. These results suggest that the activity of p53 is dependent in vivo on the amount of p53 present within cells, as it has been already demonstrated in vitro.

Caspase-independent death of meiotic and postmeiotic cells overexpressing p53: calpain involvement

“…Spermatocytes II and spermatids from MTp53 males express p53 and undergo cell death Our previous immunohistological results (Allemand et al 9 and supplementary file 1) show that ectopic p53 is present in the round spermatids of MTp53 testis. Nevertheless, in adult spermatogenesis, the MTI promoter is constitutively activated from the pachytene stage of meiosis.…”

“…The tissue was further rinsed once in PBS, fixed for 12 h in 4% paraformaldehyde-PBS and wax-embedded. TUNEL was performed as described previously 9 and tubules were scored for the presence of labeled cells (7S.E.). At least two transgenic testes per set of conditions were used with their normal counterpart.…”

“…9 In the testis of adult transgenic mice, under the control of the metallothionein I (MTI) promoter, wild-type p53 is overexpressed in round spermatids. In heterozygous MTp53-94 transgenic males, expression of ectopic p53 leads to the death of elongating spermatids and to unfertility.…”

Retinoic acid activates p53 in human embryonal carcinoma through retinoid receptor-dependent stimulation of p53 transactivation function

“…Recently, a study indicated that overexpressed wild-type p53 was in a latent form in F9 murine teratocarcinoma, suggesting a lack of selective pressure to mutate p53 in TGCTs (Lutzker and Levine, 1996). Transgenic mice homologously deleted for p53 have a high incidence of spontaneous testicular cancer and targeted over-expression or miss-expression of p53 in mice results in defects in spermiogenesis (Harvey et al, 1993;Schwartz et al, 1999;Allemand et al, 1999). This, coupled with the fact that p53 expression is restricted to the pachytene stage of meiosis, has led Chaganti and colleagues to propose that the near tetraploid TGCT arises from a meiotically arrested pachytene spermatocyte, which has been aberrantly driven to initiate mitotic cell division (Chaganti and Houldsworth, 2000).…”

Modeling the Study of DNA Damage Responses in Mice

“…Moreover, unregulated expression might even limit the generation of the mouse lines. For instance, efforts to generate p53 transgenic mice repeatedly failed due to severe defects in embryogenesis, differentiation and apoptosis (Nakamura et al, 1995, Godley et al, 1996, Allemand et al, 1999. In contrast to classical transgenic vectors, bacterial artificial chromosomes (BAC) can harbor up to 300kb of DNA and can accommodate full genes along with their regulatory elements (Shizuya et al, 1992).…”