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School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK
Correspondence should be addressed to H White-Cooper; Email: white-cooperh{at}cf.ac.uk
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Abstract |
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The anatomy and cell biology of Drosophila testes |
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Gene expression in the Drosophila testis |
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Primary spermatocytes activate a specialised transcriptional programme |
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 TopAbstractThe anatomy and cell...Gene expression in the... Primary spermatocytes activate a... Transcriptional activity in...Concluding remarksDeclaration of interestAcknowledgementsReferences |
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The genes expressed by primary spermatocytes
Microarray analysis comparing different adult tissues revealed that 
50% of the genes in the genome are expressed in testes and 8% of the transcripts detected in adults are testis-specific, while a further 5% are testis-enriched (Andrews et al. 2000, Parisi et al. 2004, Chintapalli et al. 2007). Thus, about 25% of all the genes expressed in the testes are testis-specific or testis-enriched in expression compared with other tissues. These and similar studies reveal which genes are expressed in testes, but not the roles of the encoded proteins. Whole sperm proteomics has identified around 350 protein components of mature sperm (Dorus et al. 2006). About 50% of the identified sperm proteins are testis-enriched or -specific in their transcription. Reassuringly, known sperm-specific proteins, for example β2tubulin and cytoplasmic dynein are readily identified in these data sets. Testis-specific or enriched genes can be broadly grouped into two categories: those genes with obvious paralogues expressed in other tissues (and sometimes also testes), and those without such paralogues. A short list of genes in these two classes is listed in Table 1 to give a flavour of what types of genes are expressed in Drosophila primary spermatocyte. Genes with many different gene ontology classifications appear in these lists, including metabolism, cytoskeleton, chromosome organisation etc. However, perhaps the most telling statistic from classification of testis-specific genes, and sperm proteins, by gene ontology searches is that the largest category is ‘no functional prediction’. This is particularly striking when the ontology analysis is restricted to testis-specific sperm-proteome genes present as a single copy in the fly genome; very few of these genes have associated functional predictions. Even among those with a functional prediction the prediction has rarely been tested, and most of the genes remain uncharacterised.
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The meiotic arrest loci: regulators of gene expression in primary spermatocytes
Although there must be co-ordination of varied cellular events during spermatid differentiation, genetic analysis reveals that most morphological events are independently regulated. For example, spermatid elongation involves flagellar axoneme synthesis, mitochondrial fusion and elongation of the mitochondrial derivates, and polarised growth of the plasma membrane. Spermatids mutant for fws, a subunit of the conserved oligomeric Golgi complex, or syntaxin 5, both important for endoplasmic reticulum–Golgi trafficking, initiate axoneme and mitochondrial elongation, but polarised cell growth, and thus cyst elongation, fails in these males (Xu et al. 2002, Farkas et al. 2003). In spermatids mutant for fzo, a mitofusin, mitochondrial fusion fails; however, spermatid elongation occurs (Hales & Fuller 1997). Spermatid differentiation is also, surprisingly, not dependent on completion of the meiotic divisions. Spermatocytes mutant for the cell cycle activator twine fail to undergo either meiotic division, but progress to spermatid differentiation as 4N, 16-cell cysts (White-Cooper et al. 1993).
Despite the independence of particular morphological events, genetic analysis has also revealed aspects of how the spermiogenic programme is co-ordinately regulated (Lin et al. 1996). A class of ‘meiotic arrest’ mutants have been discovered in which spermatocytes arrest development, rather than continuing into the meiotic divisions or spermiogenesis. Testes from male mutants for any of the meiotic arrest loci contain only stages of spermatogenesis up to and including mature primary spermatocytes. The primary spermatocytes in these testes do not enter the meiotic divisions neither do they initiate spermatid differentiation. The basal regions of the meiotic arrest mutant testes typically contain degenerating cells (Fig. 1). Morphologically these testes resemble that seen in testis biopsies of sterile human patients with meiosis I maturation arrest azoospermia (Meyer et al. 1992, Lin et al. 1996).
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The discovery of the tTAFs led seductively to a model for their function, whereby they simply substitute for the generally expressed TFIID, and function as basal transcription factors for transcriptional activation, specifically at the promoters of spermiogenesis genes. A simple substitution of tTAF subunits into a general TFIID complex predicts that the tTAF proteins would primarily co-localise with the masses of euchromatin in primary spermatocyte nuclei. However, the majority of tTAF protein, along with TAF1-2, is localised not to euchromatin, but rather to a subcompartment of the nucleolus (Chen et al. 2005, Metcalf & Wassarman 2007). These authors found that a minority of the tTAF staining was associated with the chromosomal masses in primary spermatocytes. Components of the generally expressed TFIID complex were either not detected in primary spermatocytes, or were chromatin associated, and excluded from the nucleolus (Metcalf & Wassarman 2007). Intriguingly, Pc, Polyhomeotic and dRing, all components of the Polycomb repression complex (PRC1), were also found to localise primarily in the nucleolus of primary spermatocytes, in a pattern coincident with that of the tTAFs (Chen et al. 2005). This nucleolar localisation of PRC1 depends on the normal activity of the tTAFs, as in tTAF mutant primary spermatocytes PRC1 components localised to chromatin but not to the nucleolus (Chen et al. 2005). These findings led to a hypothesis that the function of tTAFs in activating the testis-specific gene expression could be attributed to them being repressors of a repressor (specifically PRC1). In this scenario, tTAFs would sequester PRC1 away from testis-specific target promoters, thus de-repressing them. Testing this by chromatin immunoprecipitation on testis preparations revealed that tTAFs are bound to promoters of their target genes in primary spermatocytes (these being the only cells in the sample expressing the precipitated proteins), while in wild-type testes Pc was no more enriched at tTAF target promoters than at the promoters of non-target genes or intergenic regions. In contrast, and also in agreement with the ‘repressor of a repressor’ hypothesis, Pc was enriched at tTAF target promoters in tTAF mutant testes. The ‘tTAFs as an activator’ and ‘repressor of a repressor’ hypotheses are not mutually exclusive; it is likely that tTAFs both remove a repressor (Pc) and act as an activator, for example by recruiting the Trithorax group complex.
The aly-class gene products form testis-specific Myb-MuvB-paralogous complex
When aly was cloned it was clear that the gene was evolutionarily conserved from plants to animals (but not to fungi; White-Cooper et al. 2000). The only aly homologue to have been studied in other systems was the Caenorhabditis elegans gene lin-9, which falls into the SynMuvB genetic pathway that negatively regulates vulval induction. At that time the mechanism by which lin-9 regulates cell fate in C. elegans was not determined (Beitel et al. 2000). Genome sequencing and phylogenetic analysis revealed that aly is one of two Drosophila paralogues of the lin-9 gene, the other being mip130. Clues to the potential role of aly come from more recent analysis of its homologues. Mip130 protein was purified from ovary extracts, in a complex with Drosophila Myb, CAF1 and two other previously unknown proteins, Mip120 and Mip40 (Beall et al. 2002). This complex has since been re-purified under slightly different conditions to reveal more complex subunits, and is known as the MybMuvB (MMB) or dREAM complex (Korenjak et al. 2004, Lewis et al. 2004). The additional subunits include Drosophila Rbf (Retinoblastoma (Rb) homologue), E2F2, Dp and dLin-52. Myb, E2F2, Dp and Mip120 are all known DNA binding proteins, and the function of the dREAM/MMB complex appears to predominantly be to repress gene expression (Lewis et al. 2004). Excitingly, cloning of the C. elegans SynMuvB pathway genes has revealed a similar list of genes, whose products form the DRM complex (Harrison et al. 2006). The core DRM complex appears to comprise Lin-35 (Rb), Efl-1 (E2F2), Dpl-1 (Dp), Lin-53 (CAF1), Lin-37 (Mip40), Lin-52 and Lin-54, in addition to the aly/mip130 homologue, Lin-9. A similar complex, named LINC or DREAM has also been purified from human cells (Litovchick et al. 2007, Schmit et al. 2007). Table 3 shows the composition of these related complexes.
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The tissue-specific dREAM versus tMAC subunits are all putative DNA binding proteins. Use of testis-expressed paralogues of core complex components, along with different DNA binding proteins in testes versus somatic tissues would ensure that spermiogenesis genes are activated specifically in testes. dREAM and DRM complexes have both predominantly been linked to a role in transcriptional repression rather than activation, although an activatory role has been shown for the human complex LINC (Schmit et al. 2007). This raises the question of whether the aly-class meiotic arrest genes act directly as transcriptional activators, or as repressors of a repressor. Supporting a potential activatory role is the observation that all the aly-class proteins co-localise with euchromatin in primary spermatocytes, and that this localisation is essential for their function (White-Cooper et al. 2000, Jiang & White-Cooper 2003, Wang & Mann 2003, Jiang et al. 2007). Direct evidence for Achi/Vis acting as transcriptional activators in testes has been provided by expressing fusions of Achi/Vis with strong transactivation (VP16) and strong repression (EnR) domains. Expression of Achi-VP16 fusion proteins rescued the achi+vis mutant phenotype, while expression of Achi-EnR did not (Wang et al. 2008).
Cross-talk between the tTAFs and tMAC?
Diagnostic RNA in situ hybridisations have been used to successfully subdivide aly-class and can-class meiotic arrest mutants, and this correlated with proteins encoded aly-class genes being tMAC subunits and can-class genes being tTAFs. However mip40 does not fit neatly into this categorisation. Mip40 protein is clearly a tMAC component, however mip40 mutants are apparently can-class (Beall et al. 2007). This might indicate that Mip40 is critical for mediating interactions between the two complexes, and clearly warrants further investigation.
Testis-specific promoters
Testis-specific genes are activated only in testes and kept silent in other tissues of the fly. It is somewhat surprising that the promoter elements conferring testis specificity that have been identified to date in Drosophila are relatively small (Table 4). One of the first to be studied was the testis-specific β-tubulin isoform, β2tubulin (βTub85D). Astonishingly, a fragment consisting of only 53 bp of promoter region, plus the first 71 bp of the 5'UTR was sufficient to confer testis-specific expression on reporter genes. The UTR requirement was further refined to 23 bp. Within the promoter a 14 bp motif, β2UE1 was shown to be critical for testis-specific expression (Michiels et al. 1989). This testis-specific reporter gene expression depends on the normal function of the meiotic arrest genes, just as expression of the endogenous gene does (Hiller et al. 2001). Sequences related to the β2UE1 have been found upstream of several other testis-specific transcriptional start sites (Yang et al. 1995, Nurminsky et al. 1998), but this sequence is not found in many other testis promoters, so cannot be considered a signature sequence for testis-specific expression. The minimal sequences needed for testis-specific expression (and typically also translational control) of several other genes are listed in Table 3. These short promoters presumably contain a landing site for the testis-specific transcriptional control machinery, tTAFs and tMAC, outlined above. The fact that testis-specific control elements are so small may be important in allowing new gene duplicates to be expressed in testes. For example, the testis-specific gene Sdic evolved from duplication and fusion of the genes AnnX and Cdic, encoding an annexin and a cytoplasmic dynein intermediate chain respectively. The promoter for the newly generated Sdic gene was derived from coding regions from AnnX and intronic sequence from Cdic (Ranz et al. 2003).
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Transcriptional activity in elongating spermatids |
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17 µm; nuclei in onion stage spermatids are spherical, and about 6 µm in diameter, while the needle shaped nuclei of mature spermatids are 9 µm in length, with a maximum diameter of 0.3 µm (Tokuyasu 1974). For comparison, interphase nuclei at late syncytial blastoderm stage are 10 µm in diameter. Spermiogenesis, thus, involves a decrease in nuclear volume of 200-fold, while the meiotic divisions and nuclear reformation only deliver a 20-fold volume decrease. Spermatid nuclei first elongate and thin somewhat, which includes a fivefold volume decrease, and take on a very asymmetric shape resembling (in transverse section) an oxbow at early ‘canoe’ stage; at late canoe stage they are kidney-shaped (Tokuyasu 1974). Drosophila sperm DNA is packaged with small nuclear basic proteins, related to histone H1, termed protamine-like proteins. These lysine-rich proteins are functionally similar to the arginine-rich vertebrate protamines. Three protamine-like proteins have been described for D. melanogaster, Mst35Ba (Protamine A), Mst35Bb (Protamine B) and Mst77F (Jayaramaiah Raja & Renkawitz-Pohl 2005). All three of these proteins are found in nuclei of mature sperm. As with vertebrates, the transition from nucleosomal packaging to protamines is facilitated by transition proteins, including Tpl94D (Rathke et al. 2007). The histone–transition protein–protamine switch occurs at late canoe stage, and the major loss of nuclear volume occurs from this stage onwards. Using the single cyst RT-PCR assay on testes expressing fluorescently-tagged histones, protamines and transition proteins, we found that the comet and cup transcription occurs just before the switch, when the majority of nuclear DNA is still not highly condensed (Barreau et al. 2008). Active Pol II has also been detected specifically at the late canoe stage of spermiogenesis (Rathke et al. 2007). Although not directly tested, we assume that transcription only occurs on nucleosomally packaged chromatin. The relative timing of cessation of transcription in vertebrate spermatids and the vertebrate histone–transition protein–protamine switch has not been determined. It is not clear if the shut-off of transcription depends on the initiation of chromatin compaction, whether chromatin compaction depends on stopping transcription, or whether these events are mechanistically independent. There is a clear difference between the post-meiotic transcription in Drosophila and that in mammals. Transcription is relatively high through early stages of spermatid differentiation in mammals, shutting-off during chromatin compaction. In Drosophila, we found a general shutdown of transcription at the end of the primary spermatocyte stage; we did not detect transcript accumulation in early spermatids, rather, we found an abrupt re-activation of transcriptional capacity at mid-elongation stages. At least one of the comet genes, soti, is required for male fertility, as we found that spermatid individualisation fails in soti homozygotes (Barreau et al. 2008). It is interesting to note that soti heterozygotes are fertile, and transmit the soti mutant chromosome. Therefore, spermatid cysts in Drosophila, as in mammals, are functionally diploid, i.e. the 32 haploid soti mutant spermatids can be rescued by the normal soti allele carried by the other 32 spermatids in the cyst.
We identified 24 comet and cup genes in an in situ hybridisation screen of 1200 genes. Given our lack of systematic search strategy we have probably not identified all post-meiotically transcribed genes, and a genome scale approach is likely to yield more such genes. Analysis of the local chromatin environments of the set of 24, for example looking at gene density, clustering with co-expressed genes etc. yielded no clues as to why these genes are expressed in spermatids. The genes are found in unremarkable chromatin contexts. We have generated many transgenic lines containing genomic regions of several of the comet and cup genes. All the independent insertions mirror the endogenous expression patterns, so there appears not to be a specialised chromatin region permissive for post-meiotic transcription. As noted earlier, testis expressed genes tend to have short promoter regions, and the comet and cup genes also follow this pattern: 1 kb of genomic flanking DNA is sufficient to recapitulate the normal expression pattern (we have not evaluated shorter fragments). Further experiments are needed to identify the DNA regions driving post-meiotic expression, and of course the transcriptional activators that promote this.
Why is there post-meiotic transcription in Drosophila testes? Given that the vast majority of genes involved in spermiogenesis are transcribed in primary spermatocytes, it is interesting to ask why there is a small exceptional class. All the comet and cup transcripts are detected in primary spermatocytes, albeit at low levels, so their transcription in these cells is clearly not detrimental, although these early-produced transcripts do not persist into elongation stages. It is attractive to speculate that the post-meiotic transcription and RNA localisations are linked. In our many in situ hybridisations the only genes whose transcript levels were significantly elevated in spermatids compared to spermatocytes also showed dramatic localisation of the mRNA to the spermatid elongating ends. It is possible that other, non-localised, transcripts are also made in spermatids, but that the qualitative nature of in situ hybridisation means this is not the most appropriate method for identifying other post-meiotically transcribed genes. For the comet and cup genes, perhaps the machinery required to localise these transcripts only becomes active during spermatid elongation. Further investigation is clearly warranted to determine how and why the comet and cup transcripts localise to the growing tips of spermatids.
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Concluding remarks |
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Declaration of interest |
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Funding |
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Acknowledgements |
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Received March 2, 2009
First decision April 15, 2009
Revised manuscript received August 20, 2009
Accepted September 14, 2009
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