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From the Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania.
| Correspondence to: P. J. Wang, Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce St, Philadelphia, PA 19104 (e-mail: pwang{at}vet.upenn.edu). |
| Received for publication May 4, 2009; accepted for publication October 5, 2009. |
Infertility is a worldwide reproductive health problem, affecting men and
women about equally. Mouse genetic studies demonstrate that more than 200
genes specifically or predominantly regulate fertility. However, few genetic
causes of infertility in humans have been identified. Here, we focus on the
regulation of male fertility by X-linked, germ cell–specific genes.
Previous genomic studies reveal that the mammalian X chromosome is enriched
for genes expressed in early spermatogenesis. Recent genetic studies in mice
show that X-linked, germ cell–specific genes, such as A-kinase anchor
protein 4 (Akap4), nuclear RNA export factor 2 (Nxf2),
TBP-associated factor 7l (Taf7l), and testis-expressed gene 11
(Tex11), indeed play important roles in the regulation of male
fertility. Moreover, we find that the Taf7l Tex11 double-mutant males
exhibit much more severe defects in meiosis than either single mutant,
suggesting that these 2 X-linked genes regulate male meiosis synergistically.
The X-linked, germ cell–specific genes are particularly attractive in
the study of male infertility in humans. Because males are hemizygous for
X-linked genes, loss-of-function mutations in the single-copy X-linked genes,
unlike in autosomal genes, would not be masked by a normal allele. The genetic
studies of X-linked, germ cell–specific genes in mice have laid a
foundation for mutational analysis of their human orthologues in infertile
men.
Key words: Infertility, X chromosome, meiosis, spermatogenesis
75%) of male infertility in humans are idiopathic
(of unknown origin), and the underlying causes are believed to be genetic.
However, to date, efforts to uncover point mutations in single genes that
contribute to human spermatogenic failure have been largely unsuccessful
(Matzuk and Lamb, 2002;
Nuti and Krausz, 2008). The
slow progress in human studies could be attributed to the possibility that
even though a great number (hundreds, if not thousands) of genes specifically
regulate fertility, the contribution of mutations in each gene is likely to be
small. Therefore, the likelihood of finding a causative mutation in one
particular gene in infertile men is expected to be extremely low.
Enrichment and Deficiency of Germ Cell–Specific Genes on the X Chromosome
The transcription status of the X chromosome changes dramatically during
male germ cell development. In mammals, sex chromosomes and autosomes are
transcriptionally active in mitotically dividing spermatogonia and early
meiotic (prepachytene) spermatocytes. During meiosis, sex chromosomes undergo
meiotic sex chromosome inactivation (MSCI), and are thus transcriptionally
silenced, whereas autosomes are actively transcribed
(Solari, 1974;
Handel et al, 1994;
Turner et al, 2005). In
postmeiotic germ cells, sex chromosomes remain transcriptionally repressed
(Namekawa et al, 2006;
Turner et al, 2006). Genomic
studies have shown that germ cell–specific genes are not randomly
distributed in the genome, and that, in particular, the unique hemizygous and
transcription status of the X chromosome has shaped its germ
cell–specific gene content (Wang et
al, 2001; Khil et al,
2004; Namekawa et al,
2006; Turner et al,
2006). In summary, the X chromosome is enriched for genes
expressed prior to meiosis but is deficient in spermatogenesis genes expressed
meiotically and postmeiotically.
However, 2 recent studies added provocative episodes to the saga of the mammalian X chromosome (Mueller et al, 2008; Song et al, 2009). Many X-linked microRNAs are expressed at the pachytene stage, when MSCI occurs (Song et al, 2009). The escape from MSCI silencing by X-linked microRNAs suggests that they may contribute to MSCI itself or regulate posttranscriptional regulation of autosomal mRNAs during the meiotic and postmeiotic stages. Thirty-three multicopy gene families (a total of about 273 X-linked genes) are expressed predominantly in postmeiotic germ cells (Mueller et al, 2008). The expression level of these X-linked multicopy gene families is comparable to that of autosomal genes, suggesting that multiplication of gene copy numbers evolved to counteract transcriptional repression of the X chromosome in postmeiotic germ cells.
The importance of the X chromosome in mammalian spermatogenesis was first suggested by its enrichment of germ cell–specific genes expressed in early spermatogenesis. A systematic genomic screen identified 36 such genes from mouse spermatogonia, most of which are single-copy genes (Wang et al, 2001). Nearly one-third of these genes map to the X chromosome, suggesting that the X chromosome plays a preeminent role in early spermatogenesis. In retrospect, the number of germ cell–specific genes expressed at the spermatogonial stage is rather small (at least 36), compared with the large number of germ cell–specific genes (at least 350) expressed at the meiotic and postmeiotic stages (Griswold, 1998; Fujii et al, 2002; Schultz et al, 2003). To date, genetic studies of half of these 36 spermatogonially expressed genes by targeted inactivation have demonstrated that they play important roles in many aspects of spermatogenesis (Wang and Pan, 2007). Here, we focus on the genetic studies of 4 X-linked, germ cell–specific genes (A-kinase anchor protein 4 [Akap4], nuclear RNA export factor 2 [Nxf2], TBP-associated factor 7l [Taf7l], and testis-expressed sequence 11 [Tex11]) in mouse, because they may represent "hotspots" for mutations causing infertility in men. Because these are single-copy genes, and males are hemizygous for the X chromosome, mutations in these X-linked genes, unlike autosomal recessive mutations, would not be masked by a wild-type allele. Therefore, it is more likely one would identify causative point mutations in X-linked genes than in autosomal genes in infertile men. We will review the genetic studies of these X-linked genes in mice and humans, describe the synergistic regulation of male meiosis by 2 X-linked genes (Taf7l and Tex11), and discuss the opportunities and challenges in the study of male infertility in humans.
Akap4 Is Essential for Sperm Motility and Male Fertility
Cyclic AMP (cAMP) functions as a second messenger in the signal
transduction pathway that regulates sperm motility. The cAMP-dependent protein
kinase (PKA) is compartmentalized through its interaction with a family of
A-kinase anchoring proteins (AKAPs). AKAP4 is the most abundant protein in the
fibrous sheath, a cytoskeletal structure in the principal piece of sperm
flagellum (Carrera et al,
1994). AKAP4 interacts with AKAP3, another sperm-specific AKAP
(Brown et al, 2003). In
Akap4-deficient mice, sperm count was not reduced, but sperm were
immotile, resulting in male infertility
(Miki et al, 2002). In
Akap4 mutant sperm, fibrous sheath–associated proteins, such as
glycolytic enzymes (GAPDS) and AKAP3, were either absent or reduced in
abundance. Therefore, AKAP4 is required for structural and functional
integrity of the fibrous sheath. Mutations ablating the AKAP4 function could
cause dysplasia of the fibrous sheath (DFS) in infertile men.
Nxf2 Regulates Male Meiosis and Maintenance of Spermatogonial Stem Cells
In eukaryotes, bulk mRNAs are actively transported from the nucleus to the
cytoplasm by a family of nuclear mRNA export factors (NXFs). NXF1 is a
housekeeping gene evolutionarily conserved from yeast to humans and is
responsible for the nuclear export of bulk mRNAs
(Kang and Cullen, 1999;
Katahira et al, 1999). In
mouse, 4 Nxf genes have been identified: Nxf1, Nxf2, Nxf3,
and Nxf7 (Sasaki et al,
2005; Tan et al,
2005). Among these Nxf genes, Nxf2 is
specifically expressed in germ cells in the testis
(Wang et al, 2001). NXF2
localization in male germ cells exhibits distinct patterns: it is nuclear in
spermatogonia but localizes to the nuclear periphery (envelope) in early
spermatocytes (Lai et al,
2006; Wang and Pan,
2007). NXF2 is associated with several proteins, such as Fragile X
mental retardation syndrome 1 (FMR1), kinesin family member 17 (KIF17; a
cytoplasmic motor protein), and microtubule-associated protein 1B (MAP1B; a
microtubule-associated protein), suggesting that NXF2 might regulate mRNA
stability or trafficking (Tretyakova et
al, 2005; Lai et al,
2006; Takano et al,
2007).
Inactivation of Nxf2 in mice demonstrated that it plays a dual function in spermatogenesis: progression of meiosis and maintenance of spermatogonial stem cells (Pan et al, 2009). In a mixed genetic background, about one-third of Nxf2-deficient mice exhibited meiotic arrest, whereas the remaining mutant males had apparently normal spermatogenesis. On the C57BL/6J inbred background, Nxf2-deficient males exhibited reduced sperm count, impaired sperm motility, decreased spermatogonial proliferation, and age-dependent loss of spermatogonia, resulting in male infertility or subfertility.
Disruption of Taf7l Causes Reduced Sperm Production
Transcription factor IID (TFIID), a highly conserved general transcription
factor, is required for transcription of protein-coding genes by RNA
polymerase II. TFIID consists of TATA-binding protein (TBP) and at least 12
TBP-associated factors (TAFs; TBP-associated proteins)
(Veenstra and Wolffe, 2001;
Hochheimer and Tjian, 2003).
Testis-specific TAFs have been identified in Drosophila, mouse, and
human (Hiller et al, 2001,
2004;
Wang et al, 2001;
Wang and Page, 2002).
Interestingly, testis-specific TAFs in Drosophila are required for
meiotic progression and male fertility
(Lin et al, 1996). In mammals,
Taf7l is a testis-specific paralogue of Taf7, which is
ubiquitously expressed (Wang et al,
2001; Pointud et al,
2003). Taf7l is the ancestral gene of Taf7,
because the Taf7l coding region is interrupted by 12 introns, but the
Taf7 coding region is intronless. Thus, Taf7 appears to have
originated from the X-linked Taf7l by retroposition
(Cheng et al, 2007).
Taf7l is expressed in various types of germ cells, including
spermatogonia, spermatocytes, and spermatids
(Pointud et al, 2003).
Moreover, biochemical studies demonstrate that TAF7L replaces TAF7 in the
TFIID complex in male germ cells (Pointud
et al, 2003).
Disruption of Taf7l in mice caused a significant reduction in sperm count and sperm motility. Taf7l-deficient sperm exhibited morphologic defects in tails. The testis weight of Taf7l–/Y mice was consistently reduced by more than 10%. As a result, Taf7l-deficient males were subfertile (Cheng et al, 2007). Microarray profiling showed that the abundance of 6 genes decreased in Taf7l-deficient testes by more than 2-fold. These studies suggested that even though deficiency of TAF7L might be compensated in part by TAF7, TAF7L has evolved a specialized function in transcription in male germ cells.
TEX11 Is the First X-Linked Meiosis Factor
MSCI leads to the hypothesis that meiosis-specific factors are rarely, if
ever, encoded by the sex chromosomes. This perception was countered when TEX11
was found to be essential for male meiosis
(Yang et al, 2008).
Tex11 was originally identified as an X-linked, germ
cell–specific gene of unknown function
(Wang et al, 2001). The mouse
Tex11 gene spans about 224 kb, and thus is one of the largest genes
in the mammalian genome. The only known domain in TEX11 is a tetratricopeptide
repeat (TPR) protein-protein interaction domain, which is present in proteins
that form multimeric complexes, such as chaperones
(Blatch and Lassle, 1999).
TEX11 forms distinct foci on meiotic chromosomes in both spermatocytes and
oocytes, suggesting that it might be a meiosis-specific factor
(Yang et al, 2008). TEX11
colocalizes with recombination-related proteins. In our study, we generated
Tex11-null mice by deleting 27 (of 30) exons
(Yang et al, 2008).
Interestingly, the Tex11-null males were sterile, whereas the
Tex11-null females were subfertile. Further analyses revealed that
Tex11 is essential for male meiosis, and it plays 2 distinct
functions in meiosis: promotion of chromosomal synapsis and regulation of
crossover formation. TEX11 interacts with SYCP2, which is an integral
component of the synaptonemal complex (Yang et al,
2006,
2008). These studies suggest
that TEX11 might provide a physical link between chromosomal synapsis and
crossover formation.
Intriguingly, in another study, only the exon 3 of Tex11 was deleted in the mutant mice (Adelman and Petrini, 2008). The exon 3–deletion mutant males and females had normal fertility, suggesting that this mutant allele is not null (Adelman and Petrini, 2008). By yeast 2-hybrid assay, TEX11 was found to interact with NBS1, a component of the Mre11 complex. Although it remains to be confirmed by coimmunoprecipitation from testicular extracts or coimmunolocalization on meiotic chromosomes, the potential association between TEX11 and NBS1 is consistent with the role of TEX11 in crossover formation.
Although Tex11 is conserved in vertebrates, it also has sequence homologues (SPO22/ZIP4) in Arabidopsis and budding yeast (Tsubouchi et al, 2006; Chelysheva et al, 2007). However, TEX11 sequence homologues were not found in fission yeast, fly, or worm. SPO22 localizes as foci on yeast meiotic chromosomes (Tsubouchi et al, 2006). Like mouse TEX11, yeast SPO22 promotes both synaptonemal complex polymerization (also known as chromosomal synapsis) and crossover formation. Mutation in Arabidopsis SPO22 reduces crossover formation but does not prevent chromosomal synapsis (Chelysheva et al, 2007). Taken together, these studies demonstrate that the function of TEX11/SPO22 in meiosis is evolutionarily conserved among diverse organisms.
Synergistic Regulation of Male Meiosis by Taf7l and Tex11
We attempted to test whether Taf7l and Tex11 function
synergistically in spermatogenesis for 2 reasons. First, they exhibit the same
developmental expression pattern in male germ cells
(Wang et al, 2005). Second,
both genes are germ cell specific and map to the X chromosome, suggesting that
they might have coevolved to regulate spermatogenesis. We crossed
Taf7l and Tex11 mutant (knockout) alleles to the same X
chromosome to generate double-mutant (Taf7l–/Y
Tex11–/Y) males.
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We then determined the percentage of each stage of spermatocytes by spread
analysis (Figure 2). This
analysis showed that Taf7l Tex11 double-mutant spermatocytes, unlike
either single-mutant cell, rarely progressed to the diplotene stage.
Strikingly, the percentage of zygotene spermatocytes in the double mutant
(35%) was significantly higher than that in either single mutant (10%).
In addition, the percentage of pachytene spermatocytes with normal synapsis
was dramatically reduced in the double mutant. These data were in agreement
with the lack of late-pachytene spermatocytes in the double mutant as revealed
by histologic analysis. These studies suggested that Taf7l and
Tex11 regulate male meiosis synergistically at the zygotene and early
pachytene stages.
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Mutation screening in infertile men had been performed for several X-linked genes, such as Akap4, Taf7l, and Nxf2. However, causative mutations remain elusive. Mutation screening and immunolocalization studies in 9 men with DFS did not identify defects in AKAP4 and AKAP3 (Turner et al, 2001). In a case report, 1 infertile man with DFS appeared to be negative for AKAP4 in sperm tails and contained partial intragenic deletions in the AKAP3 and AKAP4 genes; however, further molecular analyses were necessary to define the genomic deletions (Baccetti et al, 2005). Mutation screening in the TAF7L gene was reported in 2 human studies involving 25 and 16 azoospermic patients (no sperm in semen), respectively (Stouffs et al, 2006; Akinloye et al, 2007). In both reports, the sequence changes in TAF7L were found in both azoospermic and fertile men, and thus were not causative (Stouffs et al, 2006; Akinloye et al, 2007; Tuttelmann et al, 2007). Screening of 65 azoospermic men with Sertoli cell–only syndrome did not identify mutations in NXF2 (Stouffs et al, 2008).
The failure to identify causative mutations in X-linked genes (as well as in autosomal genes) in infertile men highlights the challenges in the genetic studies of human male infertility (Matzuk and Lamb, 2002; Nuti and Krausz, 2008). First, given that hundreds, if not thousands, of genes specifically regulate male fertility, the contribution of mutations in a single gene to infertility in men would be extremely small (<1%). Therefore, it would be necessary to screen a large number (at least a hundred) of infertile patients in the future. Second, the phenotype of knockout mice serves as an informative guide in selecting infertile patients for mutation screening. The mutation screening of X-linked, germ cell–specific genes (Taf7l and Nxf2) was performed before the study of the mouse mutants, and thus only included azoospermic men. Given that inactivation of either Taf7l or Nxf2 in mice causes reduced sperm count, future mutation screening in these two genes needs to focus on oligozoospermic (reduced sperm count) rather than azoospermic men. In contrast, mutation screening of human TEX11 gene in azoospermic men with maturation arrest would be more appropriate, because Tex11 is essential for male meiosis in mice (Yang et al, 2008). Third, the ultimate challenge has been and will remain how to distinguish between a causative mutation and a polymorphism. Traditional pedigree-based linkage analysis is not applicable to the genetic study of fertility, because infertility leads to no offspring. Biochemical and molecular biologic studies would likely yield some insights into the effects of a given mutation on protein functions, but they would stop short of being a definitive proof of causality. Therefore, despite the possible complications of generating mouse models for any human disease, we propose that modeling human male infertility by generation of knockin mice with analogous mutations found in infertile men will be the most vigorous approach to test whether a sequence variant (mutation) is the cause of infertility in humans.
Acknowledgments
We thank C. Höög for the anti-SYCP1 antibody.
Footnotes
Supported by National Institutes of Health/National Institute of General Medical Sciences grant R01GM076327 (P.J.W.).
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