ROLE OF CYCLIC AMP-RESPONSE ELEMENT MODULATOR (CREM) GENE IN MALE INFERTILITY Spermatogenesis is an active process which continues during the lifetime of male individuals. During this process, germ cells give rise to mature sperm. In some cases of male infertility, the spermatogenesis is distrubed and is associated with apoptosis, and abnormal morphologic configurations in sperm. The new revelation is that the knocking out of the gene of cyclic AMP-response element modulator (CREM) is associated with developmental arrest, apoptosis, and abnormal shapes of the sperms and leads to infertility. In the homozygous mice, the development of the sperms is arrested at the postmeiotic arrrest at the first stage of of spermiogenesisLate spermatids are completely absent. The sperms in the heterologous mice still mature but the number of these cells is about 50% of those in the normal mice. Other than these changes in the testis, no gross pathology has been observed in other organs in the mice with the knocked-out gene. Several variants of CREM proteins exist. The form of CREM protein that exists in the testis activates transcription whereas those in the pineal and pituitary glands, the so-called cAMP early repressor (ICER), suppress transcription. Lack of the CREM gene leads to lack of expression of CREM-dependent genes such as genes for protamines 1 and 2, and calspermin. These genes play a significant role in the spermatogenesis. For example, during spermiogenesis, protamines 1 and 2 contribute to the compaction of the sperm head. In addition to the testis, CREM gene is also expressed in the pituitary and pineal glands. Therefore, it is still unclear whether the infertility in mice with the knocked-out gene is due solely to the role of CREM gene in the testis or its function in the pituitary is also implicated in the manifestations of CREM deficiency. Although some vaiability was observed in the serum concentration of testosterone and the amount of testicular androgens, the serum concentration of the FSH in the mice with the knocked-out gene was not significantly different from those found in the normal control mice. Besides CREM, other genes such as ER and HSP-70-2 also play a role in spermatogenesis. Members ofthe heat shock family are involved in the assembly, folding and transport of proteins in the endoplasmic reticulum, cytoplasm and mitochondria.The HSP70 family is the most conserved groups of proteins within the heat shock protein superfamily. Other members of this superfamily include, nucleolar HSP110, the highly conserved HSP90 family, mitochondrial HSP60, collagen-binding HSP47, glucose- regulated GRP75 and GRP78. Unique members of the HSP70 family are expressed during spermatogenesis. Spermatocyte-specific HSP70-2 is expressed at high levels during the meiotic phase of spermatogenesis and the testis-specfic HSC70 (HSC70t) is expressed in postmeiotic spermatids. Targeted gene disruption of the HSP70-2 resulted in failed meiosis, apoptosis of germ cells and male infertility. Male mice homozygous for the mutant allele did not synthesize HSP70-2, and did not have postmeiotic spermatids or mature sperm. However, neither meiosis nor fertility was affected in the female homozygous for the disrupted gene. The rapid progress in our understanding of the molecular mechanisms implicated in the development of sperm should make it ultimately possible to devise strategies to diagnose and treat various forms of male infertility. REFERENCES: Nantel F, Monaco L, Foulkes NS, Masquiller D, LeMeur M, Henriksen K, Dierich A, Parvinen M, Sassone-Corsi: Spermiogenesis deficiency and germ-cell apoptosis in CREM-mice. Nature, 380, 159-162, 1996 F. Nantel and P. Sassone-Corsi:CREM: A transcriptional master switch during the spermatogenesis differentiation program. Frontiers in Bioscience, 1, d266-269, 1996 CREM; Gene knockout database. Frontiers in Bioscience Blendy JA, Kaestner KH, Weinbauer GF, Nieschlag E, Shutz G: Severe impairment of spermatogenesis in mice lacking the CREM gene. Nature, 380, 162-165, 1996 Dix DJ, Allen JW, Collins BW, Mori C, Nakamura N, Poorman-Allen P, Goulding EH, Eddy EM: Targeted gene disruption of HSP70-2 results in failed meiosis, germ cell apoptosis, and male infertility. Proc Natl Acad Sci USA 93, 3264-3268, 1996 Database Links: Gene Map Locus: 10p12.1-p11.2