Molecular Human Reproduction, Vol. 8, No. 1, 24-31,
January 2002
© 2002 European Society of Human Reproduction and Embryology
Testis and spermatogenesis |
Molecular characterization of the TCP11 gene which is the human homologue of the mouse gene encoding the receptor of fertilization promoting peptide
1 Department of Medical Genetics, West China Hospital, Sichuan University, Chengdu, 610041, 2 Key Laboratory of Morbid Genomics and Forensic Medicine, Sichuan Province, 3 Department of Urology, Sichuan College of Genital Health, Sichuan Province, China and 4 Center for Human Genetics, Boston University, Boston, MA 02118, USA
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Abstract |
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A human testis-specific gene was isolated by subtractive hybridization between the cDNA pools of adult and fetal testes, followed by rapid amplification of cDNA ends (RACE). This gene sequence is highly homologous to a large portion of the mouse Tcp11 gene which is important in sperm function because it encodes the receptor for fertilization-promoting peptide (FPP). The gene was mapped to human chromosome band 6p21 by fluorescence in-situ hybridization. The 9 exon gene spans a 22.8 kp genomic DNA sequence. The mature processed message encodes a 441 amino acid protein that is highly homologous to the mouse 566 amino acid protein after the first 142 amino acids. Results of Northern blot and RT–PCR analyses of RNA extracted from human tissues revealed that the gene is only expressed in fertile adult testes, but not in azoospermic testes, fetal testes nor in other human tissues. Taken together, our results along with the mouse Tcp11 function suggest that TCP11 gene is important in sperm function and fertility.
fertilization promoting peptide/human TCP11/mouse Tcp11/testis gene expression
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Introduction |
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Spermatogenesis is a complex cell differentiation process that results in a series of dramatic molecular and morphological changes in male germ cells. This process requires the highly regulated expression of a number of genes (Willison and Ashworth, 1987
; Hecht, 1995; Sassone-Corsi, 1997). Studies of male idiopathic infertility have found that many genes on both sex chromosomes and autosomes are required for normal spermatogenesis. Some of the genes on the Y chromosome have been studied systematically (Lahn and Page, 1997, 2000; Kamp et al., 2000) and two candidate gene families on the Y chromosome are reported to be associated with azoospermia: RNA-binding motif (RBM) genes (Ma et al., 1993; Delbridge et al., 1997) and genes deleted in azoospermia (DAZ) (Reijo et al., 1995).
In addition, many other autosomal genes are also reported to be involved in spermatogenesis in both mouse and man, and these include the genes for DAZLA (the autosomal DAZ gene homologue), cAMP response element modulator (CREM), heat shock protein 70-2 (Hsp70-2) and its human homologue HSPA2 (Foulkes et al., 1992; Bonnycastle et al., 1994; Blendy et al., 1996; Cooke et al., 1996; Dix et al., 1996, 1997; Reijo et al., 1996; Ruggiu et al., 1997; Seboun et al., 1997).
Recently, more effort has been focused on the major histocompatibility (MHC) contiguous region of both species. In the human, the detailed map of the gene content of this chromosomal segment provides a number of candidate genes which may be involved in several biological processes such as spermatogenesis, development, embryogenesis, and neoplasia (Tripodis et al., 1998, 2000). This region of the mouse chromosome 17 is the distal inversion of the t-complex. The t-complex is a naturally occurring variant spanning ~15 cM of the proximal region of mouse chromosome 17, from a point near the centromere to a point between the MHC and the Pgk-2 loci, and this region accounts for ~1% of the total genome. Alternative forms are termed t-haplotypes, and are distinguished from the wild-type chromosomes by four relative inversions in the t-complex region (Hammer et al., 1989). Mutations and rearrangements in the t-complex result in a number of effects, including embryonic lethality, male sterility, recombination suppression and transmission ratio distortion (Silver, 1993; Foreijt et al., 1994). A part of this complex, within the distal inversion and extending from the mouse Hmgi(y) gene to the H2-K region, contains a number of testis-expressed genes (Abe et al., 1988; Yeom et al., 1992).
Thus, the mouse t-complex is known to harbour genes which affect male fertility. The Tcp11 gene is one of the t-complex genes isolated from the distal inversion, and is only expressed during male germ cell development and encodes the receptor for fertilization-promoting peptide (FPP). FPP (pGlu-Glu-ProNH2) is a peptide produced by the prostate gland and then secreted into seminal plasma, where it stimulates mouse and human sperm capacitation and inhibits spontaneous acrosome loss in vitro (Fraser et al., 1997; Adeoya-Osiguwa et al., 1998; Fraser, 1998a,b; Fraser and Dudley, 1999). Although the mouse Tcp11 gene has been identified (Mazarakis et al., 1991) and the human homologue has been reported to be closely linked to the ZNF76 gene and mapped to the 6p21.2–6p21.3 region (Ragoussis et al., 1992; Tripodis et al., 1998), the gene sequence of the human homologue has not been reported in any paper or on the GenBank/DDBJ/EMBL databases and the gene has not been characterized (Tripodis et al., 2000). In the present study, the human homologue of the mouse Tcp11 gene, termed TCP11, was sequenced entirely, found to encode a protein 125 amino acids shorter than that encoded by the mouse Tcp11 gene, and shown to be expressed only in fertile adult testis.
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Materials and methods |
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Subjects and RNA preparation
Fresh testicular tissue of two normal adults who died in accidents and the human fetal testicular tissue were obtained from the West China Hospital, Sichuan University with the consent of their relatives and with the approval of the Committee of Ethics of Biological and Medical Research, Sichuan University. The testis biopsy material of azoospermic patients came from the Department of Urology, Sichuan College of Genital Health. The diagnosis of azoospermia was made by sperm counting and confirmed by pathohistological examination of testis. Spermatogenesis in these testes was arrested at the spermatocyte stage. Total RNA of testicular tissues were isolated by using an RNeasy mini Kit (Qiagen, Hilden, Germany) and treated with DNase1 (RNase-free, Boehringer–Mannheim, Indianopolis, IN, USA) to eliminate DNA contamination. Pellets of total RNA were resuspended in DEPC-treated water and stored at –80°C until use.
Construction of cDNA pools
The testes of one adult and one 6 month old fetus were used for subtractive hybridization. Two primers, RTP1 and RTP2, were designed to obtain the first strand of cDNA. The primer sequences were 5'-GCTTGAGCTCGAGCTCAAGCTCAAGCTTTTTTTTTTTT(AGC)(AGCT)(AGCT)-3' and 5'-CTCCCGGGTCTAGAAGCTTTTGTTTTTTTTTT-3', respectively. Ribosome binding primer (RBSP) was designed to obtain the second strand of cDNA. Its sequence was 5'-AGGATCCGCTATGACCAGGATCCGCCGCCATG-3'. Another three primers were designed to amplify the cDNA. They were: forward primer (FP), which was the 5' terminal 22 nucleotides of RBSP; RP1, which was 5' terminal 21 nucleotides of RTP1; and RP2, which was the 5' terminal 22 nucleotides of RTP2. RTP1 and RBSP were used to synthesize double-stranded cDNA, which served as the template for PCR amplification with primer pair (FP and RP1) to obtain the cDNA pools of an adult testis and a fetus testis, labelled as AcDP1 and FcDP1 respectively. Similarly, primers (RTP2 and RBSP then RP2 and FP) were used to obtain the AcDP2 and FcDP2 cDNA pools. Then the FcDP1 and the FcDP2 pools were digested by BamHI and HindIII and the digested products were labelled as FEC1 and FEC2.
Subtractive hybridization
Subtractive hybridizations were performed between the FEC and the AcDP to obtain four subtractive cDNA pools, which then were used as templates for the PCR amplifications using four primer pairs (FP and RP1; FP and RP2; FP and RP1; FP and RP2). These PCR amplified products were separated on a 6% polyacrylamide sequencing gel for analysis. DNA bands between 200 and 1000 bp were cut out from the gel and recovered by a Qiaex II Gel Extraction kit (Qiagen) according to the manual's instructions. Isolated DNA fragments were cloned into pBluescript KS+ vector and double-stranded plasmid DNA were sequenced using an ALFexpress DNA sequencer.
cDNA cloning
The 3'-RACE primer was designed based on a cDNA sequence isolated from the subtractive cDNA pools. 3'-RACE was performed using SMART cDNA Library Construction Kit (Clontech, Palo Alto, CA, USA). In short, 3'-RACE-Ready cDNA was obtained by reverse transcription of total RNA from healthy fertile adults. Universal primer mix (UPM) provided by the kit and the gene-specific primer (GSP) 5'-GGACTTGCTCAAGCAGGAAGCAGA-3' based on the sequence of the isolated cDNA fragment were then used for 3'-RACE. The PCR reaction profile was 94°C for 2 min, then 94°C for 30 s, 68–0.5°C/cycle for 30 s, 72°C for 2 min, 10 cycles, then 94°C for 30 s, 63°C for 30 s, 72°C for 2 min for 22 cycles; followed by a final extension at 72°C for 10 min. The PCR product was then cloned into pGEM-T easy vector. Clones with the inserts of the expected size were identified by EcoRI digestion and double-stranded DNA was sequenced according to the manufacturer's protocol. Based on BLAST results of the 3'-fragment sequence and the prediction of exon location, two pairs of primers were designed to obtain the 5'-fragment of the TCP11 gene. They were: f1: 5'-AAGGCAAGGTCAAGGAGACAGTGC-3' and r1: ATTTTCAAGGTCCCAGAGAAGGAG-3'; f2: 5'-CGAAATATCCTGGCGACTCAGAGG-3' and r2: 5'-TCTGGCGTGGTAATAGCAGTGATAGC-3'. The PCR reaction profile was the same as that used for 3'-RACE. The PCR products were cloned into pGEM-T Easy vector and sequenced.
Chromosomal mapping
Mapping of the TCP11 gene was carried out with fluorescence in-situ hybridization (FISH). An 8.7 kb genomic fragment amplified by a long-range PCR was used as the probe. The primers for the PCR were f1 and r1 as mentioned above. The probe was labelled with biotin-11-dUTP (Enzo Diagnosis, Farmingdale, NY, USA) by nick-translation (Intergen, NY, USA) and hybridized to the denatured chromosomes at a final concentration of 20 ng/ml in 50% formamide, 10% dextran sulphate, 2xSSC, 0.2 mg/ml Cot-1 DNA (Gibco/BRL, Helgerman, CT, USA), 2 mg/ml salmon sperm DNA, and 2 mg/ml E.coli tRNA. The hybridized signals were detected with fluorescein isothiocyanate–avidin (Boehringer–Mannheim). Chromosomal DNA were counterstained with DAPI II (4,6-diamidino-2-phenylindole) and the slides were examined through a Zeiss fluorescent microscope with an integrating CCD camera (Photometrics. Tucson, AZ, USA). These images were captured by a Cyto Vision–Ultra Workstation (Applied Imaging, Santa Clara, CA, USA) using the Probe Software.
Genomic structure analysis
Exon–intron boundaries of the gene were identified by aligning the cDNA sequence with a corresponding genomic sequence (GenBank accession no. AL138721).
Northern blot
Multiple Tissue Northern (MTN) Blot Membranes (Clontech cat. nos. 7759-1 and 7760-1) with mRNA of 16 tissues were used to determine the tissue expression pattern of the TCP11 gene. A clone containing the TCP11 gene insert was digested with EcoRI, separated on a 2% agarose gel and the insert was recovered as a cDNA probe. Then the probe was labelled with [32P]dCTP with a Random Primed DNA Labeling kit according to the manual's protocol (Roche, Branchburg, NJ, USA) and purified with a NucleoTrap PCR Purification Kit (Clontech). Northern hybridization to the MTN membranes with the probe was then performed as described by the manual and the two membranes were then reprobed with the human ß-actin cDNA probe delivered with the kit as the control.
RT–PCR analysis
Total RNA from testicular tissues from two healthy adults, two fetuses including the one used for subtractive hybridization and two azoospermic patients were analysed for TCP11 gene expression by RT–PCR. 1 µg of total RNA was used as template for reverse transcription using cDNA First-strand Synthesis System (Gibco/BRL), and then 5 µl of reverse transcription product was used as the template for PCR. For TCP11 amplification, the forward primer and reverse primer for amplifying a 681 bp fragment were the same as those used for chromosomal mapping. The 401 bp ß-actin fragment was amplified with the following primers: 5'-GACCTGACTGACTACCTCATGA-3' and 5'-TGATCTCCTTCTGCATCCTGTC-3'. The PCR reaction profile was 94°C for 2 min, then 94°C for 30 s, 63°C for 30 s, 72°C for 90 s, for a total of 32 cycles, with a final extension at 72°C for 10 min. The PCR products were separated on a 1.5% agarose gel and analysed for RNA expression.
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Subtractive hybridization
Twenty-two fragments from the subtractive cDNA pool were obtained by polyacrylamide gel electrophoresis. Two of these fragments between 200 and 300 bp in length were cloned and sequenced. Based on the BLAST results, one was the fragment of the TnP1 gene and the other proved to be a novel human expressed sequence tag (EST).
Isolation of the human TCP11 gene
To gain the 3' fragment of the novel EST, 3'-RACE was performed and a RACE fragment of ~1.3 kb long was obtained and cloned. Three alternative clones with the 1.3 kb insert were sequenced. The 1314 nucleotide sequence was identical in each clone and contained a polyA tail and a polyadenylation signal sequence (AATAAA). Two 5' fragments of 681 and 385 bp in length were subsequently obtained by PCR amplification. The three overlapping fragments, which were the two 5' fragments and the initial 3'RACE fragment with the poly-A tail, were assembled into a 1722 bp contiguous sequence. Bioinformatics analysis is consistent with this sequence spanning a full-length cDNA including the putative initiation codon followed by an in-frame stop codon as well as a canonical polyadenylation signal AATAAA 18 bp upstream from the polyA tail. The predicted open reading frame from nucleotides 185 to 1507 is 1323 bp in length and encodes a polypeptide of 441 amino acid residues (Figure 1). Analyses suggested that it may be a membrane protein according to the detection of transmembrane regions (http://www.cbs.dtu.dk http://cubic.bioc.columbia.edu and http://www.ch.embnet.org). The transmembrane region would be from amino acid residues 270 to 287. Based on homology analyses with the gene, we found that its nucleotide and predicted protein sequences share 79 and 78% identity with mouse Tcp11 respectively (Figure 2). Therefore the novel gene was regarded as the homologue of the mouse gene Tcp11 and termed TCP11. The nucleotide sequence of the gene has been deposited in the GenBank Database under accession no. AF269223.
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Localization of the TCP11 gene to chromosome 6p21
The chromosome location of the human TCP11 gene was determined by FISH. One hundred metaphases were analysed by recording fluorescent signals on DAPI-banded chromosomes and comparing them with photographs of Q-banded chromosome images. Figure 3
shows a typical dual hybridization signal localized at 6p21. This assignment is in full accordance with the result of mapping by bioinformatic approaches using the UniGene database.
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Genomic structure of human TCP11
The genomic structure of human TCP11 gene was obtained from a 155 539 bp sequence submission (GenBank accession no. AL138721) which is from Clone RP11-174N3 on chromosome 6 and includes the entire TCP11 gene sequence. The exon–intron boundaries and intron sizes are shown in Table I
and Figure 4. All boundaries conform to the GT/AG rule (Mount, 1982).
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Exclusion expression of TCP11 gene in testis
The results of the Northern blot hybridization with a cDNA probe (681 bp cDNA fragment of the TCP11 gene) on a human multiple tissue Northern (MTN) membrane is shown in Figure 5
. A strong signal representing a transcript of ~1.75 kb was detected in the testis lane, but no signal was detected in spleen, thymus, prostate, ovary, small intestine, colon or peripheral leukocyte mRNA. The second human MTN (Clontech cat. no. 7760-1) was probed in the same way, but no signal was identified in heart, brain, placenta, lung, liver, skeletal muscle, kidney or pancreas mRNA (not shown). Therefore, TCP11 mRNA appears to be exclusively expressed in testis, with no expression at detectable levels in other tissues.
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To examine the expression of the TCP11 gene in normal, pathological and developing testis, RT–PCR experiments with mRNA from different testicular tissues were performed (Figure 6
). As shown in the figure, the expected amplified products were present in samples from both of the fertile adults but not in samples from the two fetuses or from the azoospermic patients. This result suggests that the gene may play an important role in normal sperm function and male fertility.
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Discussion |
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At the DNA level, it is now known that the region of mouse chromosome 17 where the t-complex maps has undergone two major non-overlapping inversions, a proximal and a distal inversion (Artzt et al., 1982
; Hermann et al., 1986) and two smaller inversions, a centromeric inversion located between the centromere and the proximal as well as a middle located between the proximal and distal inversions (Hammer et al., 1989). These rearrangements are responsible for the low rate of recombination between wild-type and t-chromosomes in the region of the t-complex. Rare recombination events generate partial t-haplotypes comprising proximal, central or distal portions of the t-complex (Fox et al., 1985) and these are useful tools for the genetic analysis of this region (Lyon and Meredith, 1964).
In mouse, the t-complex, where the t-haplotype differs from the wild-type chromosome with respect to the four relative inversions, contains genes known to influence male, but not female, fertility. When male mice heterozygous for the t-chromosome mate with wild type females, most offspring will possess the t-chromosome and males with two t-haplotypes are invariably sterile, indicating a link between t-complex genes and sperm function. Several proteins encoded by t-complex genes have been localized in the sperm flagellum, suggesting roles relating to motility (Olds-Clark and Johnson, 1993; Hu et al., 1995; Harrisson et al., 1998; Fraser and Dudley, 1999). A recent study (Redkar et al., 2000) has shown that the genes in the first and fourth inversions of the t-complex synergistically mediate sperm capacitation and interactions with the oocyte and indicated the existence of the two major t-male sterility factors, S1 and S2, within inversions 1 and 4 respectively. Both S1 and S2 contain mutations altering sperm function, including motility, capacitation, binding to the zona pellucida, binding to the oocyte membrane and penetration of the zona pellucida-free oocyte. Therefore it seems clear that each factor contains multiple genes contributing to sterility (Redkar et al., 2000). Given the existence of human homologues for many genes in the t-complex and the prevalence of `male factor' infertility, information obtained about the t-complex and t-complex genes will not only provide insights into basic biological mechanisms, but may also be of future clinical relevance.
Evidence indicates that the history of the four inversions of the t-complex are different (Hammer et al., 1989). Human homologues of mouse markers in the proximal inversion are located on the long arm of chromosome 6, while human homologues of markers in the distal inversion are located on the short arm of chromosome 6, and both the human and mouse homologous regions contain MHC genes (Willison and Ashworth, 1987; Willison et al., 1987; Bibbins et al., 1989; Tripodis et al., 1998). In humans, a 2.5 Mb chromosomal segment flanking the centromeric end of the MHC region has been cloned and physically mapped. The contiguous sequence contains the genes encoding GLO1, CBSP, p21, HSU09564 serine kinase, ZNF76, RPS10, HMGI(Y), BAK and Hset. The gene order of the GLO1-HMGI(Y) segment with respect to the centromere is similar to the gene order in the mouse t-chromosome distal inversion, indicating that there is conservation in gene content but not gene order between human and mouse in this region (Tripodis et al., 1998, 2000). Sporadic cases have been reported associating the HLA region in humans with spontaneous abortion, transmission distortion and infertility, all of which are characteristics of the mouse t-complex (Kostyu, 1994). By FISH, the human TCP11 gene was also located in this region 6p21. It is striking that testis-expressed genes appear to cluster in this region which is homologous in both species, and it would be interesting to investigate the presence of more testis-expressed genes in this region. A recent study has shown a familial t(6;21)(p21.1;p13) translocation associated with male-only sterility, although no particular gene was found to be disrupted (Paoloni-Giacobino et al., 2000). Two interesting questions remain concerning the nature of the relationship between these genes, and whether a common mechanism regulates their expression.
As for the mouse Tcp11 gene, recent studies suggest that the protein of Tcp11 gene is the receptor for FPP, which stimulates capacitation and increases fertilizing ability in vitro, when added to uncapacitated mouse and human sperm suspensions (Fraser et al., 1997; Adeoya-Osiguwa et al., 1998; Fraser, 1998a,b,c). Current evidence indicates that FPP and the Tcp11 protein act by modulating the activity of adenylyl cyclase and hence production of cAMP, a signal transduction pathway shown to be important in the acquisition of fertilizing ability (Adeoya-Osiguwa et al., 1998; Fraser, 1998b,c). Anti-Tcp11 antibodies have the same effect as FPP on mouse spermatozoa, that is significant stimulation of cAMP production in sperm membranes, permeabilized cells and intact cells, and Gln-FPP, a competitive inhibiting FPP, also competitively inhibits these responses to the Fab fragment (Adeoya-Osiguwa et al., 1998).
The structure and expression analyses of the novel human TCP11 gene suggest that it is the homologue of the mouse Tcp11 gene. Based on the homology analysis of the gene, its nucleotide sequence and protein exhibit 79 and 78% identity with mouse Tcp11 gene. The result of detection of transmembrane regions indicated that this gene encodes a membrane protein. Furthermore, this gene was shown to have a testis-specific pattern of expression similar to that described for mouse Tcp11. Mouse Tcp11 is exclusively expressed in mouse male germ cells with transcripts that are first detected in late pachytene spermatocytes/early secondary spermatocytes among cells differentiating into mature spermatozoa. Pachytene spermatocytes are known to be the most transcriptionally active male germ cells (Mazarakis et al., 1991; Hosseini et al., 1994).
In addition, Northern blot and RT–PCR analyses indicated that a relationship exists between the human TCP11 gene and male fertility. Firstly, Northern blots with range of 16 human tissues showed that, like its mouse homologue, the human TCP11 gene is exclusively expressed in male germ cells, where human spermatogenesis occurs. Secondly, RT–PCR analysis of testicular tissue from two fertile adults and two fetuses revealed that the gene is expressed only in fertile adult testis but not in fetal testis. This suggests that the gene is only expressed after the onset of puberty. Finally, the absence of gene expression in the testes of azoospermic patients also indicates that expression of this gene is associated with, or is the product of, normal spermatogenesis. Together this evidence indicates that TCP11 plays an important role in human sperm function and fertility just as FPP and Tcp11 do in the mouse. Given the prevalence of male factor infertility, this ligand–receptor pair may be important in studies of infertility and could also provide a novel target for male contraception.
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This work was supported by the grants of the National Natural Science Foundation of China (nos. 39970404 and 39993420).
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5 To whom correspondence should be addressed. E-mail: szzhang{at}mcwcums.com
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References |
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Submitted on May 14, 2001;
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