Transplantation of Wild-Type Spermatogonia Leads to Complete Spermatogenesis in Testes of Cyclic 3′,5′-Adenosine Monophosphate Response Element Modulator-Deficient Mice1

Abstract

The cAMP response element modulator (CREM) gene encodes transcription factors that are highly expressed in spermatids. A deficiency of the CREM gene leads to male infertility in mice due to round spermatid maturation arrest. However, CREM is also expressed in testicular Sertoli cells. We investigated whether CREM deficiency affects the germ line alone or whether the testicular environment is also dependent on CREM function. We examined the restoration of donor-derived spermatogenesis in CREM-deficient testes after transfer of wild-type spermatogonia (16 animals) and after transplantation of germ cells from CREM-deficient or heterozygous donors into spermatogenic tubules of wild-type hosts (16 and 12 animals). Six wk after endogenous spermatogenesis had been depleted by busulphan treatment, spermatogonia were transferred via the rete testis. Production of donor-derived germ cells in the deficient recipients was confirmed by testicular histology and polymerase chain reaction (PCR) analysis of testis fragments 7 and 13 wk after germ cell transfer. Sperm with donor genotype, as detected by PCR, also were flushed from the epididymis. Germ cell transfer using heterozygous donors was also successful. CREM-deficient germ cells largely failed to colonize wild-type recipient testes. According to these findings, germ cell differentiation is dependent on CREM function. The testicular environment of CREM-deficient mice is not essentially affected and is able to support complete spermatogenesis in the presence of wild-type germ cells.

Korean ginseng induces spermatogenesis in rats through the activation of cAMP-responsive element modulator (CREM)

“…Germ cell differentiation is dependent on CREM function (14). The function of CREM in human spermatid development suggests that altered CREM expression could be associated with defects in spermatid maturation in some cases of idiopathic male infertility (15).…”

Development of the caput epididymidis studied by expressed proteins (a glutamate transporter, a lipocalin and ?-galactosidase) in the c-ros knockout and wild-type mice with prepubertally ligated efferent ducts

“…Preliminary studies with tissue fixed and stained en bloc with substrate (X-Gal: 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside; Wistuba et al 2002) revealed inadequate penetration of substrate to the centre of the block. In order to be certain of the observation of all activity, cryo-sections and a modified method of Buckner et al (1999) were used.…”

Crem Activator Isoforms in Normal and Impaired Human Spermatogenesis Analyzed by Real Time RT-PCR

“…Infertile men exhibit a substantial reduction of CREM activators [Lin et al 1998, Peri and Serio 2000, Steger et al 1999 and inaccurately spliced CREM transcripts . It seems that CREM gene deficiency affects the germ line alone, since the testicular environment in CREM deficient mice is able to support complete spermatogenesis in the presence of wild-type germ cells [Wistuba et al 2002]. In our study, we have shown very low levels of mRNA for CREM activator isoforms in SCOS samples or in the interstitium of the normal gonad.…”

“…CREM null mice display spermatogenic arrest at the early haploid phase and fail to reach the round spermatid stage and hence spermatozoa are absent [Blendy et al 1996, Nantel et al 1996. Previous reports suggested that CREM may be important for spermatid development and a stage-specific regulation of spermatogenesis in rodents, primates and humans [Wistuba et al 2002, Lin et al 1998, Steger et al 1999. Infertile men exhibit a substantial reduction of CREM activators [Lin et al 1998, Peri and Serio 2000, Steger et al 1999 and inaccurately spliced CREM transcripts .…”