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Regulation of Spermatogenesis by Crem

 

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Male germ cell differentiation requires a highly cell-specific gene expression programme that is achieved by unique chromatin remodelling, transcriptional control, and the expression of testis-specific genes or isoforms. The regulatory processes governing gene expression in spermatogenesis have fundamentally unique requirements, including meiosis, ongoing cellular differentiation and a peculiar chromatin organization. The signalling cascades and the downstream effectors contributing to the programme of spermatogenesis are currently being unravelled, revealing the unique features of germ cell regulatory circuits. This paper reports on the unique role that CREM exerts as a master regulator. Targeted inactivation of the genes encoding CREM and ACT has been achieved. ACT selectively associates with KIF17b, a kinesin motor protein highly expressed in germ cells. It has been found that KIF17b directly determines the intracellular localization of ACT. Thus, the activity of a transcriptional co-activator is intimately coupled to the function of a kinesin via tight regulation of its intracellular localization. The conservation of these elements and of their regulatory functions in human spermatogenesis indicates that they are likely to provide important insights into understanding the molecular mechanisms of human infertility.The cAMP-responsive element modulator (CREM) is involved in regulating gene expression in haploid spermatids. Transcriptional activity of the CREM protein is thought to be regulated by activator of CREM in the testis (ACT). Applying RT-PCR and in situ hybridization, cell-specific gene expression of ACT was demonstrated in man, cynomolgus monkey and mouse. During normal spermatogenesis, RT-PCR revealed a strong signal in all three species. We sequenced monkey ACT cDNA and demonstrated that the putative amino acid sequence is highly conserved between these species. In situ hybridization demonstrated ACT mRNA in mid and late pachytene spermatocytes and in round spermatids. Among four infertile men with round spermatid maturation arrest (RSMA), only one patient revealed a strong signal for ACT, while three patients displayed a weak signal for both RT-PCR and in situ hybridization, although germ cells normally expressing ACT were present in these patients. In addition, CREM knockout mice known to be infertile due to RSMA also exhibited only a weak amplification product for ACT cDNA. ACT mRNA was barely detectable in some round spermatids, but was completely absent in pachytene spermatocytes. Database search revealed two and one CRE within the putative human and mouse ACT promoters respectively. Our findings indicate a conserved function of ACT during the evolution of mammalian spermatogenesis and suggest a role for CREM in ACT transcriptional regulation.

PMID: 14742698 [PubMed - in process]