This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kimmins, S. Articles by Sassone-Corsi, P. Search for Related Content PubMed PubMed Citation Articles by Kimmins, S. Articles by Sassone-Corsi, P.

Testis-specific transcription mechanisms promoting male germ-cell differentiation

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS–INSERM-Université Louis Pasteur, BP 163, 67404 Illkirch, Strasbourg, France

Correspondence should be addressed to P Sassone-Corsi; Email: paolosc{at}igbmc.u-strasbg.fr

	Abstract

Top Abstract Introduction Spermatogenesis Transcription factor CREM in... Conclusions Acknowledgements References

 
Male germ-cell differentiation requires spermatogenic stage- and cell-specific gene expression that is achieved by unique chromatin remodeling, transcriptional control and the expression of testis-specific genes or isoforms. Recent findings have shown that the testis has specialized transcription complexes that coordinate the differentiation program of spermatogenesis. There are male germ cell-specific differences in the components of the general transcription machinery. These include upregulated expression of the TATA-binding protein (TBP) family and its associated cofactors. Importantly, a member of the TBP family, TBP-like factor (TLF), has a distribution pattern that is dependent on the spermatogenic cycle and is essential for spermatogenesis. Interestingly TBP-associated factor (TAF7), a factor of the transcription factor (TF)IID complex, is exchanged at a critical stage in germ cell development for the testis-specific paralogue TAF7L. A compelling amount of data has established that cAMP-response-element modulator (CREM), a transcription factor responsive to the cAMP signal transduction pathway, drives expression of key testis-specific genes. In this review we summarize recent advances in the transcription machinery that is testis-specific, gene-selective and necessary for the process of spermatogenesis.

	Introduction

Top Abstract Introduction Spermatogenesis Transcription factor CREM in... Conclusions Acknowledgements References

 
Specialized mechanisms have evolved to control the complex differentiation program of mammalian spermatogenesis. These include altered levels of general transcription factors and the expression of unique testis isoforms of transcription activators. Transcriptional activation, as a means of gene regulation, is directed by multisubunit transcription factor complexes that interact with gene promoters and the chromatin complex. Transcription in germ cells during spermatogenesis follows a carefully regulated program corresponding to a series of differentiation events occurring in spermatogonial cells, spermatocytes and haploid spermatids (Sassone-Corsi 2002). Arrest of transcription in spermiogenesis coincides with changes in the acquisition of the transcriptional machinery and chromatin compaction at the transition from round to elongating spermatids. In the testis, specific gene expression is in part achieved through transcription factor CREM (cAMP-response-element modulator), whose gene structure and function is conserved in mice and humans (Masquilier et al. 1993). Alterations in the general transcription machinery also show that testis-specific transcription machinery has evolved. In this review we focus on the recent advances in our laboratory in the area of transcription factors, their cofactors, and proteins connecting to the general transcription machinery that are unique to the testis and how they might regulate and coordinate expression of genes that are required for sperm development and function.

	Spermatogenesis

Top Abstract Introduction Spermatogenesis Transcription factor CREM in... Conclusions Acknowledgements References

 
The process of spermatogenesis follows an endocrine-regulated developmental program that features the transformation of an undifferentiated diploid stem cell into highly differentiated haploid spermatozoa (Fig. 1). The differentiation of germ cells into spermatozoa occurs in the tubular seminiferous epithelium, and depends on a complex paracrine dialogue with Sertoli cells (Skinner et al. 1991). Testosterone secreted by Leydig cells under the influence of pituitary-secreted luteinizing hormone (LH), and follicle-stimulating hormone (FSH), acting on Sertoli cells, stimulates gene transcription and the secretion of peptides that promote germ-cell differentiation. Biochemical stimulation of germ cells is thought to occur via the secretion of regulatory molecules from Sertoli cells such as growth factors and proteases (Griswold 1998).

View larger version (32K): [in this window] [in a new window]   Figure 1 Spermatogenesis follows a carefully orchestrated differentiation program that depends on trancriptional regulation. The transcription phase begins in spermatogonia. Meiotic cells have a high level of transcription that is promoted by histone acetylation, making DNA accessible. Elevated transcription in meiotic cells is required for chromosome congression, recombination and desynapsis. In post-meiotic spermatids there is a second round of histone acetylation and transcription, followed by the sequential replacement of histones by transition proteins then protamines. This altered chromatin architecture leads to arrested transcription and differentiation into elongated spermatids.

The post-meiotic developmental phase, spermiogenesis, involves the differentiation of spermatids into spermatozoa. This phase is a remarkable process as germ cells undergo an enormous morphogenetic transformation involving DNA compaction, cytoplasmic ejection and acrosome and flagellar formation. Male germ cell-specific nuclear proteins, the transition proteins and protamines, sequentially replace histones, to allow for DNA compaction and to permit reshaping of the round spermatid nucleus (Wouters-Tyrou et al. 1998). The highly ordered process required for production of the male gamete involves precise steps of transcriptional control to govern the changing patterns of gene expression.

	Transcription factor CREM in spermatogenesis

Top Abstract Introduction Spermatogenesis Transcription factor CREM in... Conclusions Acknowledgements References

 
Essential role of CREM in spermatogenesis
Transcription factors of the cAMP-response-element binding protein (CREB)–CREM family target genes with cAMP response elements (CREs) constituted by the palindromic consensus sequence TGACGTCA (Sassone-Corsi et al. 1988). CREM is a master controller gene for spermatogenesis, as demonstrated by targeted mutation in the mouse (Nantel et al. 1996). CREM knock-out mice are sterile due to arrest of spermatogenesis at the round spermatid stage (Blendy et al. 1996, Nantel et al. 1996). Infertility in these mice is attributable to the lack of expression of key post-meiotic genes required for differentiation such as protamines 1 and 2, transition proteins 1 and 2, proacrosin, and calspermin, among others (Sun et al. 1995, Sassone-Corsi 1998). These genes contain CREs in their promoter that are recognized by CREM (Kistler et al. 1994, Sun et al. 1995, Steger et al. 1999). In CREM-null mice these genes fail to be expressed resulting in arrested cell differentiation and eventually spermatocytes that undergo apoptosis (Nantel et al. 1996).

The major domains of CREM include the C-terminal leucine zipper domain necessary for DNA-binding and homo- and heterodimerization, and the glutamine-rich activation domain, which functions as a region for cofactor interactions and flanks the phosphoacceptor domain, the P-box (Radhakrishnan et al. 1997) (Fig. 2). In somatic cells phosphorylation at serine-117 controls the activation state of CREM and can be achieved by various kinases that are in turn stimulated by hormones, growth factors, intracellular calcium and cell stress factors (De Cesare et al. 1999). In contrast, in germ cells, the activation of CREM is not dependent on phosphorylation (Fimia et al. 1999).

View larger version (17K): [in this window] [in a new window]   Figure 2 Functional domains and isoforms of CREM. The activation domain contains glutamine-rich regions, Q1 and Q2, which facilitate protein–protein interactions. Within the activation domain is the P-(phosphorylation) box containing the target residue for PKA phosphorylation, among other phosphoacceptor sites. The DNA-binding domain contains a basic region (BD), required for binding to CRE sequences, and the leucine zipper (LZ) region that permits dimerization.

The specific role of CREB in the testis is still elusive. A physiological function is however suggested by the expression pattern in Sertoli cells where it follows spermatogenic-dependent waves; expression is high from stages I to VIII, then decreases through stages IX–XII (Waeber et al. 1991). Using an adenovirus-assisted approach the function of CREB in Sertoli cells was examined. A dominant-negative CREB that could not undergo phosphorylation on serine 133 was injected into rat seminiferous tubules. Interestingly, Sertoli cells were targeted, but the mutant had a negative effect on germ cells. In treated mice Sertoli cells were normal, however spermatocytes underwent apoptosis resulting in arrested spermatogenesis and a 75% reduction in spermatids (Scobey et al. 2001). A probable explanation for these results is that the dominant-negative CREB is also able to counteract CREM, and subsequently blocked the essential function of CREM in spermatogenesis. In support of this interpretation, it is important to stress that CREB-null mice display normal fertility (Bourtchuladze et al. 1994).

Regulation and differential activation of CREM in germ cells and somatic tissues
Regulation of CREM in the testes is attributable to secretion of FSH. Exposure of golden hamster, a seasonal breeder, to a short photoperiod – or disruption of the hypothalamic – gonadal axis in rats – ablates CREM transcription in germ cells. When hamsters were either subjected to a long photoperiod to induce secretion of FSH, or administered exogenous FSH, CREM transcripts rapidly accumulated in the testes (Foulkes et al. 1993). The molecular mechanism underlying the rapid and sensitive response to FSH is based on post-transcriptional events in which CREM transcripts are modified by alternative usage of three polyadenylation sites. The 3' untranslated region of CREM contains ten AUUUA destabilizer elements and upon FSH stimulation there is a switch of polyadenylation to the most 5' site, an event that confers greater stability to the transcript (Foulkes et al. 1993). Thus, accumulation of CREM transcripts at puberty is not the result of FSH-induced transcription, but is remarkably due to an alteration in post-transcriptional processing. The effect of FSH on CREM is indirect, as germ cells lack FSH receptors, and is therefore likely to be part of the complex paracrine circuitry that occurs between germ cells and Sertoli cells.

There are several differences in the mechanisms underlying CREM activation in germ cells versus somatic cells. Activation of CREM in Sertoli cells is stimulated by FSH binding its G-protein-coupled receptor. The resultant signal transduction cascade leads to activation of protein kinase A (PKA) or mitogen-activated protein kinases (MAPKs). In the nucleus, phosphorylation of CREM at serine 117 permits its interaction with coactivators. These then link CREM to the general transcription machinery via association with core proteins of the preinitiation complex TFIIB (Foulkes et al. 1993, Eckner et al. 1994, Sassone-Corsi 1995). A major difference with somatic cells is that in germ cells, CREM does not require phosphorylation at serine 117 in order to function as a transcriptional activator, nor association with CBP (Fimia et al. 1999). Rather, CREM activity in post-meiotic germ cells is enhanced by its association with the LIM-only protein ACT (activator of CREM in the testis) (Fimia et al. 1999, Palermo et al. 2001). ACT is composed of four-and-a-half LIM domains, each containing two zinc finger motifs that facilitate protein–protein interactions (Fimia et al. 1999). Most LIM proteins have been determined to have roles in cell differentiation and development by influencing either transcriptional or cytoskeletal components. During spermatogenesis in mice and humans the expression of CREM and ACT is spatially and temporally paired (Fimia et al. 1999, Palermo et al. 2001), and together they function as powerful transcriptional activators. A further role for zinc-finger-containing proteins in transcription is indicated by the discovery of testicular zinc finger protein (TZF) and its splice variant, TZF-L. Interestingly, the gene for these proteins contains CREs in the promoter and distribution is restricted to the nucleus of pachytene-stage cells, suggesting they may have a role in gene transcription related to formation of the synaptonemal complex (Ishizuka et al. 2003).

CREM, ACT and KIF17b: functional cooperation in the regulation of testis gene transcription
A natural progression was to determine what regulatory proteins control the function of the CREM–ACT pair. In a yeast two-hybrid screen using a testis cDNA library, there was a strong interaction between ACT and a kinesin protein highly similar to an isoform found in the brain, KIF17 (Macho et al. 2002). The testis isoform was named KIF17b. Immunofluorescence localization experiments using squashed segments from defined stages of the mouse seminiferous tubules revealed a spermatogenic-stage-specific cellular distribution of KIF17b and ACT. At the round spermatid stage ACT is present in the nucleus, then beginning at stage VIII in elongating spermatids it can be detected in the cytoplasm (Fig. 3). Similarly, KIF17b is present in the nucleus of round spermatids and by stage VIII is primarily present in the cytoplasm of early elongated spermatids. This parallel localization pattern of KIF17b and ACT is in line with a transport role for this kinesin functioning as a regulator of CREM transcription by removing ACT from the nucleus. In support of this, in transfected cells KIF17b can inhibit expression of the CREM target genes calspermin and angiotensin-converting enzyme by sequestering ACT in the cytosol (Macho et al. 2002).

View larger version (77K): [in this window] [in a new window]   Figure 3 Immunofluorescent localization using an ACT-targeting antibody was performed on squash preparations from segments of defined stages of the mouse seminiferous tubule obtained by transillumination-assisted microdissection. In round spermatids at stage VI ACT is nuclear, but during spermatid elongation from stage IX onward, ACT is predominantly in the cytoplasm. Relocalization of ACT from the nucleus to the cytoplasm of elongating spermatids temporally correlates with the cessation of CREM-dependent transcription.

Unique features of the testis general transcriptional machinery
There are many examples of testis-specialized protein homologues that display regulated distribution patterns and serve as components of the general transcription machinery. These factors often show an expression pattern that is cell-compartment-specific (nuclear versus cytoplasmic), and dependent on the stage of spermatogenesis. In male germ cells, transcription is controlled by activators such as CREM and by the general transcription initiation complex that assembles around the transcription start site. Initiation of transcription requires basal transcription factors (TFIIA, -B, -D, -E and -F) and their associated factors (TBP-associated factors, TAFs), to interact at promoter elements which often include a TATA-box. Proteins that cluster at the TATA-box are collectively referred to as TBPs (TATA-box-binding proteins). Although the TBP complex is important for RNA polymerase II interaction with promoters and initiation of transcription, it is not essential (Hernandez 1993, Wieczorek et al. 1998).

Exquisite tissue-specific mechanisms of gene expression operate in male germ cells, as revealed by important modifications to the general transcription machinery. For example, TFIIA/ß-like factor is only expressed in the testis, and TFIIB, TBP and RNA polymerase II are upregulated in round spermatids (Schmidt & Schibler 1995, Upadhyaya et al. 1999). This increased expression reflects the greater need for the transcription machinery to fulfil the requirement for the rapid and large amount of transcription that occurs in haploid spermatids in preparation for chromatin condensation.

TBP and TBP-like factor (TLF) show differential patterns of distribution and function in spermatogenesis
TLF, otherwise known as TRF2, TLP or TRP, is similar in sequence to TBP but has a unique distribution in spermatogenesis. Transcription reactions in vitro have demonstrated that TLF is not able to substitute for TBP (Moore et al. 1999), due to differences in the DNA interaction region (Berk 2000). However, TLF does interact with the general transcription factors TFIIA and TFIIB, and has been shown to bind the pes-10 promoter (Kaltenbach et al. 2000). These observations have led to the hypothesis that TLF may have a special role in gene transcription from TATA-less promoters, interestingly a feature of various post-meiotic CREM target genes such as CYP51 (Rozman et al. 1999).

Interest in TLF function in spermatogenesis was generated by the discovery that its expression is high in the testis relative to other tissues. Confirming a physiological role for TLF during spermatogenesis, mice null for TLF show arrested spermiogenesis, increased apoptosis of haploid spermatids, abnormal acrosomes, disrupted heterochromatic chromocenters and altered expression of testis-specific genes; all of which contribute to the sterile phenotype (Martianov et al. 2001, Zhang et al. 2001). In a recent study (Martianov et al. 2002), the expression and distribution of TLF was compared with that of TBP and was found to be more tightly regulated in terms of cell type and intracellular distribution. Expression of TLF increases in late-pachytene spermatocytes, coinciding with the appearance of CREM. TLF protein is detected in the cytoplasm of early-pachytene spermatocytes, then becomes principally nuclear and remains in the nucleus of round spermatids. TLF then returns to the cytoplasm in elongating spermatids, coinciding with arrested transcription. Confocal analysis shows that TLF is associated with both heterochromatin and euchromatin (Martianov et al. 2002), suggesting that it may function as both a repressor and activator of transcription in spermatogenesis. In transfected eukaryotic cells, TLF has been shown to function only as a repressor (Moore et al. 1999). As in spermatogenesis, a role for TLF has been indicated in embryogenesis. Studies using RNA interference to block TLF in Caenorhabditis elegans resulted in embryos with arrested development that failed to proceed to gastrulation. This phenotype was attributed to the lack of expression of genes required for differentiation (Kaltenbach et al. 2000).

As with TLF, TBP expression increases in late-pachytene spermatocytes, but in contrast to TLF, TBP is present in all developing sperm types and is not localized to the cytoplasm (Schmidt & Schibler 1995, Zhang et al. 2001, Martianov et al. 2002). As for many classical transcription factors, TBP is associated with transcriptionally active euchromatin but not heterochromatin (Martianov et al. 2002).

There are three key pieces of evidence that tie TLF to CREM-driven transcription. First, the timing of TLF expression increases just prior to the appearance of CREM mRNA. Second, the phenotype of TLF-null mice is reminiscent of the CREM-deficient animals and third, various CRE-containing post-meiotic genes lack a TATA-box in their promoter. Since TLF has been shown to form a stable complex with the TFIIA subunit (Teichmann et al. 1999), it was logical to determine if CREM interacts with TFIIA. Indeed in a recent study activator isoforms of CREM were shown to interact with TFIIA and the expression of CREM and TFIIA was found to be coordinately regulated (De Cesare et al. 2003). Therefore it is likely that CREM, in association with TFIIA, forms a complex with TLF to promote transcription from post-meiotic promoters.

Remodeling of the TFIID complex via switching of TAF7 for TAF7L
A component of the TBP multicomplex, TFIID is required for transcription of protein coding genes. A factor associated with TFIID, TAF7, has been found to have a testis-specific paralogue, TAF7L (Pointud et al. 2003). Immunofluorescence localization of TAF7 and TAF7L indicates that their presence in the nucleus in haploid spermatids does not overlap and therefore they appear to have mutually exclusive roles. To explain further, TAF7 is present in the nucleus in developing germ cells until the late-pachytene stage, after which it becomes cytoplasmic. Coincident with the movement of TAF7 to the cytoplasm is the appearance of TAF7L in the nucleus where it remains until the transition to elongating spermatids. As confirmation of these immunolocalization studies, immunoprecipitation with an antiserum against TBP, known to recognize TFIID, demonstrated that TAF7L, being nuclear, coimmunoprecipitated with TBP, whereas the cytoplasmic TAF7 did not (Pointud et al. 2003). The switch within the transcription machinery to include a testis-specific paralogue reflects the intriguing complexity of post-meiotic transcription (Fig. 4).

View larger version (24K): [in this window] [in a new window]   Figure 4 The testis has specialized transcription complexes that coordinate the differentiation program of spermatogenesis. Transcription factor CREM is required for the expression of many post-meiotic genes. It associates with the spermatid-specific coactivator protein, ACT, that enhances CREM-dependent transcription in a phosphorylation-independent manner. The activity of ACT is in turn regulated by a kinesin protein, KIF17b, that determines the subcellular localization of ACT. TLF is a member of the TBP protein family which is essential for spermatogenesis and has a distribution pattern that is dependent on the spermatogenic cycle. Like TBP, it interacts with the general transcription factor TFIIA. There are also germ cell-specific alterations in the components of the general machinery. For example, TAF7, a factor of the TFIID complex, is exchanged at a critical stage in germ cell development for the testis-specific paralogue TAF7L.

	Conclusions

Top Abstract Introduction Spermatogenesis Transcription factor CREM in... Conclusions Acknowledgements References

	Acknowledgements

Top Abstract Introduction Spermatogenesis Transcription factor CREM in... Conclusions Acknowledgements References

 
We are grateful to all members of the Sassone-Corsi laboratory for stimulating discussions and for their contributions to this work. S K and N K were supported by fellowships from the Foundation Pour la Recherche Médicale and the European Molecular Biology Organization respectively. Our studies are supported by grants from Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire Régional, Fondation de la Recherche Médicale, Université Louis Pasteur, Human Frontier Science Program (RG-240) and La Ligue contre le Cancer.

	References

Top Abstract Introduction Spermatogenesis Transcription factor CREM in... Conclusions Acknowledgements References

 

Berk AJ 2000 TBP-like factors come into focus. Cell 103 5–8.[CrossRef][Web of Science][Medline]

Blendy JA, Kaestner KH, Weinbauer GF, Nieschlag E & Schutz G 1996 Severe impairment of spermatogenesis in mice lacking the CREM gene. Nature 380 162–165.[CrossRef][Medline]

Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G & Silva AJ 1994 Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79 59–68.[CrossRef][Web of Science][Medline]

Carpenter AT 1987 Gene conversion, recombination nodules, and the initiation of meiotic synapsis. Bioessays 6 232–236.[CrossRef][Web of Science][Medline]

Daniel PB, Rohrbach L & Habener JF 2000 Novel cyclic adenosine 3' ,5' -monophosphate (cAMP) response element modulator theta isoforms expressed by two newly identified cAMP-responsive promoters active in the testis. Endocrinology 141 3923–3930.[Abstract/Free Full Text]

De Cesare D, Jacquot S, Hanauer A & Sassone-Corsi P 1998 Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene. PNAS 95 12202–12207.[Abstract/Free Full Text]

De Cesare D, Fimia GM & Sassone-Corsi P 1999 Signaling routes to CREM and CREB: plasticity in transcriptional activation. Trends in Biochemical Sciences 24 281–285.[CrossRef][Web of Science][Medline]

De Cesare D, Fimia GM, Brancorsini S, Parvinen M & Sassone-Corsi P 2003 Transcriptional control in male germ cells: general factor TFIIA participates in CREM-dependent gene expression. Molecular Endocrinology 17 2554–2565.[Abstract/Free Full Text]

Delmas V, van der Hoorn F, Mellstrom B, Jegou B & Sassone-Corsi P 1993 Induction of CREM activator proteins in spermatids: down-stream targets and implications for haploid germ cell differentiation. Molecular Endocrinology 7 1502–1514.[Abstract/Free Full Text]

Eckner R, Ewen ME, Newsome D, Gerdes M, DeCaprio JA, Lawrence JB & Livingston DM 1994 Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes and Development 8 869–884.[Abstract/Free Full Text]

Fimia GM, De Cesare D & Sassone-Corsi P 1999 CBP-independent activation of CREM and CREB by the LIM-only protein ACT. Nature 398 165–169.[CrossRef][Medline]

Fimia GM, De Cesare D & Sassone-Corsi P 2000 A family of LIM-only transcriptional coactivators: tissue-specific expression and selective activation of CREB and CREM. Molecular and Cellular Biology 20 8613–8622.[Abstract/Free Full Text]

Foulkes NS, Borrelli E & Sassone-Corsi P 1991 CREM gene: use of alternative DNA-binding domains generates multiple antagonists of camp-induced transcription. Cell 64 739–749.[CrossRef][Web of Science][Medline]

Foulkes NS, Mellstrom B, Benusiglio E & Sassone-Corsi P 1992 Developmental switch of CREM function during spermatogenesis: from antagonist to activator. Nature 355 80–84.[CrossRef][Medline]

Foulkes NS, Schlotter F, Pevet P & Sassone-Corsi M 1993 Pituitary hormone FSH directs the CREM functional switch during spermatogenesis. Nature 362 264–267.[CrossRef][Medline]

Griswold MD 1998 The central role of Sertoli cells in spermatogenesis. Seminars in Cell and Developmental Biology 9 411–416.

Guardavaccaro D, Kudo Y, Boulaire J, Barchi M, Busino L, Donzelli M, Margottin-Goguet F, Jackson PK, Yamasaki L & Pagano M 2003 Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo. Developmental Cell 4 799–812.[CrossRef][Web of Science][Medline]

Hernandez N 1993 TBP a universal eukaryotic transcription factor? Genes and Development 7 1291–1308.[Free Full Text]

Ishizuka M, Ohshima H, Tamura N, Nakada T, Inoue A, Hirose S & Hagiwara H 2003 Molecular cloning and characteristics of a novel zinc finger protein and its splice variant whose transcripts are expressed during spermatogenesis. Biochemical and Biophysical Research Communications 301 1079–1085.[CrossRef][Web of Science][Medline]

Kaltenbach L, Horner MA, Rothman JH & Mango SE 2000 The TBP-like factor CeTLF is required to activate RNA polymerase II transcription during C elegans embryogenesis. Molecular Cell 6 705–713.[CrossRef][Web of Science][Medline]

Kistler MK, Sassone-Corsi P & Kistler WS 1994 Identification of a functional cyclic adenosine 3' ,5' -monophosphate response element in the 5' -flanking region of the gene for transition protein 1 (TP1), a basic chromosomal protein of mammalian spermatids. Biology of Reproduction 51 1322–1329.[Abstract]

Macho B, Brancorsini S, Fimia GM, Setou M, Hirokawa N & Sassone-Corsi P 2002 CREM-dependent transcription in male germ cells controlled by a kinesin. Science 298 2388–2390.[Abstract/Free Full Text]

Martianov I, Fimia GM, Dierich A, Parvinen M, Sassone-Corsi P & Davidson I 2001 Late arrest of spermiogenesis and germ cell apoptosis in mice lacking the TBP-like TLF/TRF2 gene. Molecular Cell 7 9–15.

Martianov I, Brancorsini S, Gansmuller A, Parvinen M, Davidson I & Sassone-Corsi P 2002 Distinct functions of TBP and TLF/TRF2 during spermatogenesis: requirement of TLF for heterochromatic chromocenter formation in haploid round spermatids. Development 129 945–955.

Masquilier D, Foulkes NS, Mattei MG & Sassone-Corsi P 1993 Human CREM gene: evolutionary conservation, chromosomal localization and inducibility of the transcript. Cell Growth and Differentiation 4 931–937.[Abstract]

Molina CA, Foulkes NS, Lalli E & Sassone-Corsi P 1993 Inducibility and negative autoregulation of CREM: an alternative promoter directs the expression of ICER, an early response repressor. Cell 75 875–886.[CrossRef][Web of Science][Medline]

Monaco L, Foulkes NS & Sassone-Corsi P 1995 Pituitary follicle-stimulating hormone (FSH) induces CREM gene expression in Sertoli cells: involvement in long-term desensitization of the FSH receptor. PNAS 92 10673–10677.[Abstract/Free Full Text]

Moore PA, Ozer J, Salunek M, Jan G, Zerby D, Campbell S & Lieberman PM 1999 A human TATA binding protein-related protein with altered DNA binding specificity inhibits transcription from multiple promoters and activators. Molecular and Cellular Biology 19 7610–7620.[Abstract/Free Full Text]

Nantel F & Sassone-Corsi P 1996 CREM: a transcriptional master switch during the spermatogenesis differentiation program. Frontiers in Bioscience 1 266–269.

Nantel F, Monaco L, Foulkes NS, Masquilier D, LeMeur M, Henrik-sen K, Dierich A, Parvinen M & Sassone-Corsi P 1996 Spermio-genesis deficiency and germ-cell apoptosis in CREM-mutant mice. Nature 380 159–162.[CrossRef][Medline]

Ortega S, Prieto I, Odajima J, Martin A, Dubus P, Sotillo R, Barbero JL, Malumbres M & Barbacid M 2003 Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nature Genetics 35 25–31.[CrossRef][Web of Science][Medline]

Palermo I, Litrico L, Emmanuele G, Giuffrida V, Sassone-Corsi P, De Cesare D, Maria Fimia G, D’A’Agata R, Calogero AE & Travali S 2001 Cloning and expression of activator of CREM in testis in human testicular tissue. Biochemical and Biophysical Research Communications 283 406–411.[CrossRef][Web of Science][Medline]

Parra MT, Viera A, Gomez R, Page J, Carmena M, Earnshaw WC, Rufas JS & Suja JA 2003 Dynamic relocalization of the chromosomal passenger complex proteins inner centromere protein (INCENP) and aurora-B kinase during male mouse meiosis. Journal of Cell Science 116 961–974.[Abstract/Free Full Text]

Pointud JC, Mengus G, Brancorsini S, Monaco L, Parvinen M, Sassone-Corsi P & Davidson I 2003 The intracellular localisation of TAF7L, a paralogue of transcription factor TFIID subunit TAF7, is developmentally regulated during male germ-cell differentiation. Journal of Cell Science 116 1847–1858.[Abstract/Free Full Text]

Radhakrishnan I, Perez-Alvarado GC, Parker D, Dyson HJ, Montminy MR & Wright PE 1997 Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator:coactivator interactions. Cell 91 741–752.[CrossRef][Web of Science][Medline]

de Rooij DG 2001 Proliferation and differentiation of spermatogonial stem cells. Reproduction 121 347–354.[Abstract]

Rosenberg MP, Aversa CR, Wallace R & Propst F 1995 Expression of the v-Mos oncogene in male meiotic germ cells of transgenic mice results in metaphase arrest. Cell Growth and Differentiation 6 325–336.[Abstract]

Rozman D, Fink M, Fimia GM, Sassone-Corsi P & Waterman MR 1999 Cyclic adenosine 3' ,5' -monophosphate(cAMP)/cAMP-responsive element modulator (CREM)-dependent regulation of cholesterogenic lanosterol 14alpha-demethylase (CYP51) in spermatids. Molecular Endocrinology 13 1951–1962.[Abstract/Free Full Text]

Sassone-Corsi P 1995 Transcription factors responsive to cAMP. Annual Review of Cell and Developmental Biology 11 355–377.[CrossRef][Web of Science][Medline]

Sassone-Corsi P 1998 CREM: a master-switch governing male germ cells differentiation and apoptosis. Seminars in Developmental Biology 9 475–482.

Sassone-Corsi P 2002 Unique chromatin remodeling and transcriptional regulation in spermatogenesis. Science 296 2176–2178.[Abstract/Free Full Text]

Sassone-Corsi P, Visvader J, Ferland L, Mellon PL & Verma IM 1988 Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-responsive element. Genes and Development 2 1529–1538.[Abstract/Free Full Text]

Schmidt EE & Schibler U 1995 High accumulation of components of the RNA polymerase II transcription machinery in rodent spermatids. Development 121 2373–2383.[Abstract]

Scobey M, Bertera S, Somers J, Watkins S, Zeleznik A & Walker W 2001 Delivery of a cyclic adenosine 3' ,5' -monophosphate response element-binding protein (creb) mutant to seminiferous tubules results in impaired spermatogenesis. Endocrinology 142 948–954.[Abstract/Free Full Text]

Skinner MK, Norton JN, Mullaney BP, Rosselli M, Whaley PD & Anthony CT 1991 Cell–cell interactions and the regulation of testis function. Annals of the New York Academy of Sciences 637 354–363.[Web of Science][Medline]

Steger K, Klonisch T, Gavenis K, Behr R, Schaller V, Drabent B, Doenecke D, Nieschlag E, Bergmann M & Weinbauer GF 1999 Round spermatids show normal testis-specific H1t but reduced cAMP-responsive element modulator and transition protein 1 expression in men with round-spermatid maturation arrest. Andrology 20 747–754.

Stehle JH, Foulkes NS, Molina CA, Simonneaux V, Pévet P & Sassone-Corsi P 1993 Adrenergic signals direct rhythmic expression of transcriptional repressor CREM in the pineal gland. Nature 365 314–320.[CrossRef][Medline]

Sun Z, Sassone-Corsi P & Means AR 1995 Calspermin gene transcription is regulated by two cyclic AMP response elements contained in an alternative promoter in the calmodulin kinase IV gene. Molecular and Cellular Biology 15 561–571.[Abstract]

Teichmann M, Wang Z, Martinez E, Tjernberg A, Zhang D, Vollmer F, Chait BT & Roeder RG 1999 Human TATA-binding protein-related factor-2 (hTRF2) stably associates with hTFIIA in HeLa cells. PNAS 96 13720–13725.[Abstract/Free Full Text]

Upadhyaya AB, Lee SH & DeJong J 1999 Identification of a general transcription factor TFIIAalpha/beta homolog selectively expressed in testis. Journal of Biological Chemistry 274 18040–18048.[Abstract/Free Full Text]

Waeber G, Meyer TE, LeSieur M, Hermann HL, Gerard N & Habener JF 1991 Developmental stage-specific expression of cyclic adenosine 3' ,5' -monophosphate response element-binding protein CREB during spermatogenesis involves alternative exon splicing. Molecular Endocrinology 5 1418–1430.[Abstract/Free Full Text]

Wieczorek E, Brand M, Jacq X & Tora L 1998 Function of TAF(II)-containing complex without TBP in transcription by RNA polymerase II. Nature 393 187–191.[CrossRef][Medline]

Wouters-Tyrou D, Martinage A, Chevaillier P & Sautiere P 1998 Nuclear basic proteins in spermiogenesis. Biochimie 80 117–128.[Medline]

Yuan L, Liu JG, Zhao J, Brundell E, Daneholt B & Hoog C 2000 The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Molecular Cell 5 73–83.[CrossRef][Web of Science][Medline]

Zhang D, Penttila TL, Morris PL, Teichmann M & Roeder RG 2001 Spermiogenesis deficiency in mice lacking the Trf2 gene. Science 292 1153–1155.[Abstract/Free Full Text]

This article has been cited by other articles:

				M. Carlile, D. Swan, K. Jackson, K. Preston-Fayers, B. Ballester, P. Flicek, and A. Werner Strand selective generation of endo-siRNAs from the Na/phosphate transporter gene Slc34a1 in murine tissues Nucleic Acids Res., April 1, 2009; 37(7): 2274 - 2282. [Abstract] [Full Text] [PDF]

				G. Delbes, D. Chan, P. Pakarinen, J. M. Trasler, B. F. Hales, and B. Robaire Impact of the Chemotherapy Cocktail Used to Treat Testicular Cancer on the Gene Expression Profile of Germ Cells from Male Brown-Norway Rats Biol Reprod, February 1, 2009; 80(2): 320 - 327. [Abstract] [Full Text] [PDF]

				S. A. Ranpura, U. Deshmukh, and P. P. Reddi NF45 and NF90 in Murine Seminiferous Epithelium: Potential Role in SP-10 Gene Transcription J Androl, March 1, 2008; 29(2): 186 - 197. [Abstract] [Full Text] [PDF]

				H. Yoshioka, C. B. Geyer, J. L. Hornecker, K. T. Patel, and J. R. McCarrey In Vivo Analysis of Developmentally and Evolutionarily Dynamic Protein-DNA Interactions Regulating Transcription of the Pgk2 Gene during Mammalian Spermatogenesis Mol. Cell. Biol., November 15, 2007; 27(22): 7871 - 7885. [Abstract] [Full Text] [PDF]

				M. Godmann, V. Auger, V. Ferraroni-Aguiar, A. D. Sauro, C. Sette, R. Behr, and S. Kimmins Dynamic Regulation of Histone H3 Methylation at Lysine 4 in Mammalian Spermatogenesis Biol Reprod, November 1, 2007; 77(5): 754 - 764. [Abstract] [Full Text] [PDF]

				D. T. Carrell, B. R. Emery, and S. Hammoud Altered protamine expression and diminished spermatogenesis: what is the link? Hum. Reprod. Update, May 1, 2007; 13(3): 313 - 327. [Abstract] [Full Text] [PDF]

				Y. Cheng, M. G. Buffone, M. Kouadio, M. Goodheart, D. C. Page, G. L. Gerton, I. Davidson, and P. J. Wang Abnormal Sperm in Mice Lacking the Taf7l Gene Mol. Cell. Biol., April 1, 2007; 27(7): 2582 - 2589. [Abstract] [Full Text] [PDF]

				S. Kimmins, C. Crosio, N. Kotaja, J. Hirayama, L. Monaco, C. Hoog, M. van Duin, J. A. Gossen, and P. Sassone-Corsi Differential Functions of the Aurora-B and Aurora-C Kinases in Mammalian Spermatogenesis Mol. Endocrinol., March 1, 2007; 21(3): 726 - 739. [Abstract] [Full Text] [PDF]

				A. Gautier-Stein, C. Zitoun, E. Lalli, G. Mithieux, and F. Rajas Transcriptional Regulation of the Glucose-6-phosphatase Gene by cAMP/Vasoactive Intestinal Peptide in the Intestine: ROLE OF HNF4{alpha}, CREM, HNF1{alpha}, and C/EBP{alpha} J. Biol. Chem., October 20, 2006; 281(42): 31268 - 31278. [Abstract] [Full Text] [PDF]

				M. El-Alfy, L. Azzi, J. Lessard, E. Lavergne, M. Pelletier, and C. Labrie Stage-Specific Expression of the Atce1/Tisp40{alpha} Isoform of CREB3L4 in Mouse Spermatids J Androl, September 1, 2006; 27(5): 686 - 694. [Abstract] [Full Text] [PDF]

				S. Kuwahara, A. Ikei, Y. Taguchi, Y. Tabuchi, N. Fujimoto, M. Obinata, S. Uesugi, and Y. Kurihara PSPC1, NONO, and SFPQ Are Expressed in Mouse Sertoli Cells and May Function as Coregulators of Androgen Receptor-Mediated Transcription Biol Reprod, September 1, 2006; 75(3): 352 - 359. [Abstract] [Full Text] [PDF]

				H. Wang, B. L. Sartini, C. F. Millette, and D. L. Kilpatrick A Developmental Switch in Transcription Factor Isoforms During Spermatogenesis Controlled by Alternative Messenger RNA 3'-End Formation Biol Reprod, September 1, 2006; 75(3): 318 - 323. [Abstract] [Full Text] [PDF]

				Y.-T. Lin and P. H. Yen A novel nucleocytoplasmic shuttling sequence of DAZAP1, a testis-abundant RNA-binding protein RNA, August 1, 2006; 12(8): 1486 - 1493. [Abstract] [Full Text] [PDF]

				R. Oliva Protamines and male infertility Hum. Reprod. Update, July 1, 2006; 12(4): 417 - 435. [Abstract] [Full Text] [PDF]

				G. L. Christensen, S. P. Wooding, I. P. Ivanov, J. F. Atkins, and D. T. Carrell Sequencing and haplotype analysis of the Activator of CREM in the Testis (ACT) gene in populations of fertile and infertile males. Mol. Hum. Reprod., April 1, 2006; 12(4): 257 - 262. [Abstract] [Full Text] [PDF]

				J. L. Marmar and S. Benoff The safety of ultrasonically guided testis aspiration biopsies and efficacy of use to predict varicocelectomy outcome Hum. Reprod., August 1, 2005; 20(8): 2279 - 2288. [Abstract] [Full Text] [PDF]

				J. Hyun, H. Jasper, and D. Bohmann DREF Is Required for Efficient Growth and Cell Cycle Progression in Drosophila Imaginal Discs Mol. Cell. Biol., July 1, 2005; 25(13): 5590 - 5598. [Abstract] [Full Text] [PDF]

				G. Wrobel and M. Primig Mammalian male germ cells are fertile ground for expression profiling of sexual reproduction Reproduction, January 1, 2005; 129(1): 1 - 7. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kimmins, S. Articles by Sassone-Corsi, P. Search for Related Content PubMed PubMed Citation Articles by Kimmins, S. Articles by Sassone-Corsi, P.