Regulation of
Spermatogenesis by Crem
Repression of pain
sensation by the Transsriptional
Rerulator Dream
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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]
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