[Frontiers in Bioscience 1, d266-269, September 1, 1996]
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CAVEAT LECTOR



CREM: A TRANSCRIPTIONAL MASTER SWITCH DURING THE SPERMATOGENESIS DIFFERENTIATION PROGRAM

François Nantel and Paolo Sassone-Corsi

Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, BP 163, ILLKIRCH Cedex, C.U. de Strasbourg, France

Received 08/17/96; Accepted 08/21/96; On-line 09/01/96

5. CREM KNOCKOUT MICE

The physiological role of CREM has been addressed with the development of mice in which the CREM gene is disrupted by homologous recombination (17, 18). Heterozygous mutant mice appeared normal and healthy although there was a slight reduction in the average litter size. Analysis of sperm from heterozygous male mice show a 46% reduction in sperm number, a 35% decrease in the ratio of motile spermatozoa and a two-fold increase in the proportion of spermatozoa with aberrant structures.

Homozygous CREM mice appear healthy and present no obvious physical aberrations or weight loss. While the homozygous females are fertile, the males however are sterile. Testis weight in homozygous mice is 25% less than those found in wild-type animals and the seminal fluid was completely devoid of spermatozoa. Histological analysis of seminiferous tubules show that spermatogenesis in CREM-deficient mice is interrupted at the very early spermatid stage (Figure 1). Elongating spermatid and spermatozoa are completely absent, while pre-meiotic germ cells and somatic Sertoli and Leydig cells appear normal. In the testis from CREM-mutant mice, there is a ten-fold increase in multi-nucleated giant cells undergoing apoptosis. Analysis of gene expression in the testis shows that expression of post-meiotic genes is decreased in the CREM-deficient mice. These include genes encoding the protamines, transition proteins and RT7. Moreover, transcripts for Krox-20, Krox-24 and calspermin genes are also absent in testis from heterozygous animals.

Figure 1: Histological analysis of testis from 8 weeks-old wild-type (left) and CREM knockout mice (right). Note the absence of developing spermatids and spermatozoa and the presence of multi-nucleated giant cells in the mutant animal.

These results indicate that CREM is essential for the differentiation program of spermiogenesis. The absence of CREM prevents the expression of many haploid-specific genes and the germ cells go into apoptosis following their meiotic division. The observation that FSH and testosterone levels are not reduced in CREM-mutant mice (18) suggests that these animals may constitute tools for the study of male infertility with normal gonadotropin level.

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