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Cyclic adenosine 3',5'-monophosphate-responsive element modulator gene expression in germ cells of normo- and
1Department of Clinical Physiopathology, University of Florence School of Medicine, Italy. a.peri@dfc.unifi.it
Abstract:
In about one third of infertile men the cause of impaired spermatogenesis is not known. Spermatogenesis appears to be mediated at least in part by the pituitary gonadotropins, which activate the cAMP-dependent signaling pathway. The end point of this pathway is the activation of nuclear transcription factors, such as cAMP-responsive element-binding protein and cAMP-responsive element modulator (CREM). These factors, upon binding to gene sequences identified as cAMP response elements, modulate the expression of germ cell-specific genes that, in turn, promote the completion of spermatogenesis. The expressions of the cAMP-responsive element-binding protein and CREM genes create different isoforms, which can be divided into two groups: activators or repressors of gene regulation. Only CREM repressors are expressed in premeiotic germ cells in mice, whereas a switch to the expression of the CREM activator tau is observed from postmeiotic germ cells onward. Completion of germ cell maturation appears to be dependent on this phenomenon. Recently, mice lacking CREM gene expression have been generated. These animals were infertile and presented a developmental arrest of germ cell maturation at the stage of early spermatid. In this report we demonstrate that CREM gene expression also occurs in human germ cells. In particular, we determined by RT-PCR that a switch from the expression of CREM repressors to CREM activators is present in postmeiotic germ cells in normospermic men. Conversely, in oligoazoospermic patients only the expression of CREM repressors was detected. These data were confirmed by in situ hybridization studies in which transcripts for CREM activators were detected in postmeiotic germ cells in testis specimens showing conserved spermatogenesis, but not in specimens showing maturation arrest at the spermatid stage. Thus, our results indicate that the lack of a switch in the expression of CREM gene isoforms may be related to impaired spermatogenesis in humans.
Insights
A switch in gene expression, specifically from cAMP-responsive element modulator (CREM) repressors to activators, is crucial for normal sperm development. Its absence in infertile men suggests a cause for impaired spermatogenesis.
Area of Science:
- Reproductive Biology
- Molecular Genetics
- Human Physiology
Background:
- The cause of impaired spermatogenesis remains unknown in about one-third of infertile men.
- Spermatogenesis involves pituitary gonadotropins activating the cAMP signaling pathway, leading to transcription factor activation.
- cAMP-responsive element-binding protein and cAMP-responsive element modulator (CREM) regulate germ cell-specific genes essential for spermatogenesis.
Purpose of the Study:
- To investigate the role of CREM gene expression and its isoforms in human spermatogenesis.
- To determine if alterations in CREM isoform expression are associated with male infertility.
Main Methods:
- Reverse transcription polymerase chain reaction (RT-PCR) was used to analyze CREM gene expression in human germ cells.
- In situ hybridization was employed to localize CREM activator transcripts in testicular tissues.
- Comparison of gene expression patterns between normospermic men and oligoazoospermic patients.
Main Results:
- A switch from CREM repressor to activator expression was observed in postmeiotic germ cells of normospermic men.
- Oligoazoospermic patients exclusively showed expression of CREM repressors, lacking the switch to activators.
- CREM activator transcripts were detected in postmeiotic germ cells with normal spermatogenesis but absent in cases of maturation arrest.
Conclusions:
- The switch in CREM gene isoform expression is vital for the completion of human spermatogenesis.
- A failure to switch from CREM repressors to activators may be a contributing factor to impaired spermatogenesis in humans.
- This finding offers a potential molecular basis for unexplained male infertility.