MBE Advance Access originally published online on October 25, 2006
Molecular Biology and Evolution 2007 24(1):281-287; doi:10.1093/molbev/msl161
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Research Articles |
Morphological Change Caused by Loss of the Taxon-Specific Polyalanine Tract in Hoxd-13
* Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan; and
Laboratory of Gene Expression and Regulation, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
E-mail: sueda{at}biol.s.u-tokyo.ac.jp.
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Abstract |
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Sequence comparison of Hoxd-13 among vertebrates revealed the presence of taxon-specific polyalanine tracts in amniotes. To investigate their function at the organismal level, we replaced the wild-type Hoxd-13 gene with one lacking the 15-residue polyalanine tract by using homologous recombination. Sesamoid bone formation in knock-in mice was different from that in the wild type; this was observed not only in the homozygotes but also in the heterozygotes. The present study provides the first direct evidence that taxon-specific homopolymeric amino acid repeats are involved in phenotypic diversification at the organismal level.
Key Words: homopolymeric amino acid repeats • polyalanine tract • Hoxd-13 • mouse model
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Simple tandem repeats of a particular amino acid, also known as homopolymeric amino acid repeats, are a very common feature in eukaryotic proteins (Green and Wang 1994
; Albá and Guigó 2004; Faux et al. 2005). These repeats are also present in transcription factors. It is widely accepted that transcription factors are evolutionarily well conserved. However, the evolutionary conservation is only limited to the DNA-binding domain of transcription factors. Among the vertebrates, some transcription factors show striking features of sequence diversity, that is, the presence or absence of homopolymeric amino acid repeats (Sumiyama et al. 1996; Nakachi et al. 1997). Thus, homopolymeric amino acid repeats are identified as the representatives of sequence diversity in transcription factors. It has been reported that some types of homopolymeric amino acid repeats such as those of alanine, glutamine, glycine, and proline can modulate protein–protein interactions and/or transcriptional regulation (Mitchell and Tjian 1989; Emili et al. 1994; Gerber et al. 1994; Imafuku et al. 1998; Xiao and Jeang 1998; Wilkins and Lis 1999; Dunah et al. 2002; Freiman and Tjian 2002); however, to date, their biological implications remain unknown.
Aberrant expansions of homopolymeric amino acid repeats are known to cause diseases in humans (Gatchel and Zoghbi 2005). In synpolydactyly (OMIM number 186000
[OMIM]
), a limb abnormality involving the duplication of fingers and the presence of webbing between the fingers are observed (Muragaki et al. 1996; Goodman 2002). This malformation has been shown to result from a mutation in the Hoxd-13 gene. In the amino terminal transactivation domain of Hoxd-13 in healthy humans, there is a homopolymeric amino acid repeat comprising 15 alanine residues. In affected individuals, an expansion of 7–14 alanine residues is observed in this polyalanine tract. Moreover, the severity of the disease phenotype is proportional to the number of extra alanine residues (Goodman et al. 1997; Bruneau et al. 2001). Polyalanine expansion in the Hoxd-13 gene is also observed in the mouse synpolydactyly homolog, spdh, and it causes similar defects in mouse autopods (Johnson et al. 1998). Our preliminary comparison revealed that among mammals, the homopolymeric alanine repeats in Hoxd-13 were highly conserved, whereas nonmammalian vertebrates showed strikingly different features from the mammalian homologues; these included a truncated polyalanine tract in nonmammalian amniotes or the complete absence of the polyalanine tract in other vertebrates. In this study, we addressed the phenotypic diversity among vertebrates focusing on the polyalanine tract in Hoxd-13. We generated Hoxd-13 knock-in mice lacking the 15-residue polyalanine tract to seek any morphological changes introduced by the presence or absence of the alanine repeats.
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Materials and Methods |
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Generation of a Hoxd-13 Knock-in Mouse
Mouse Hoxd-13 was isolated from a FIXII phage genomic library (Stratagene, La Jolla, CA), and a 4.8-kb XhoI fragment, including the Hoxd-13–coding region, was subcloned. To create a mouse Hoxd-13 gene that completely lacked the 15-residue homopolymeric alanine repeats, a SgrAI-SapI DNA fragment, including this polyalanine tract, was replaced with a synthetic double-stranded oligonucleotide that was produced by annealing with 5'-CCGGTGTTCGCGGGGACACATTCCGGACGCTCCACGTTCGCTTACCCAGGTACCTCTGAGCGCACAGGCTCTTCG-3' and 5'-CGACGAAGAGCCTGTGCGCTCAGAGGTACCTGGGTAAGCGAACGTGGAGCGTCCGGAATGTGTCCCCGCGAACA-3'. A synonymous KpnI site was also introduced. To construct the long homologous arm of the targeting vector, a 1.5-kb XhoI-BglII fragment of the subclone that lacked the polyalanine-coding region was fused to the 5' terminal of the neo cassette, and a 7.8-kb SacII-XhoI fragment containing the 5'-flanking region of the Hoxd-13 gene was linked at the further 5' terminal. The neomycin-resistance gene driven by the phosphoglycerate kinase promoter (neo cassette) and the diphtheria toxin fragment A (DT-A) gene driven by the MC1 promoter were used as the markers of positive and negative selection, respectively.
E14.1 ES cells (embryonic stem cells derived from 129P2) were maintained on a feeder layer of primary cultured mouse embryonic fibroblasts in Dulbecco's modified Eagle's medium containing 15% heat-inactivated fetal calf serum, 6 µl/ml 2-mercaptoethanol, 3 µg/ml sodium bicarbonate, and recombinant leukemia-inhibitory factor to maintain pluripotency. Ten micrograms of the targeting vector DNA linearized with SalI were transfected into the ES cells by electroporation. After a day, the cells were subjected to G418 selection at 400 µg/ml for 7 days. Homologous recombination was monitored by polymerase chain reaction (PCR) and Southern blot analysis. For the Southern blot analysis, the genomic DNA was digested with KpnI and hybridized with NX and XE probes, as described previously (Dollé et al. 1993). The NX probe was prepared by the PCR amplification of mouse DNA by using 5'-GCATTGTTTTCCTTGAGCG-3' and 5'-CCTACTGCTGGCAAGAAGTT-3' as the primers. The XE probe was prepared by the XhoI and EcoRI digestion of the PCR product of mouse DNA amplified using 5'-GGTCCATTTCTCAGGTTTCC-3' and 5'-TGGGAGGAGGCAGAAGTTTT-3' as the primers. The presence or absence of the polyalanine tract was examined by PCR using 5'-GTGTTCGCGGGGACACATTC-3' and 5'-TGCGACATGCGGCAGCTGTA-3' as the primers. After the removal of the neo cassette by using Cre recombinase, chimeric mice were generated by blastocyst injection. The noon of the day on which a vaginal plug was observed was designated as E0.5.
Skeletal Analysis
The soft tissues of the mice were cleared with 1% KOH, and the bones were stained with alizarin red S by the standard method (Nagy 2002). The wrist region of adult mice at 63 days postpartum (dpp) was CT scanned using a microfocal X-ray industrial CT scanner (model TX225-Actis, Tesco, Tokyo, Japan) at the University Museum, The University of Tokyo. Slice thickness was set at either 25 µm or 13 µm; each CT image was reconstructed in a 512 x 512 matrix with a pixel size of either 25 µm or 13 µm. The produced volume data sets consisted of isotropic voxels, and the 25- and 13-µm data sets were used to visualize the entire manus or only the sesamoid bone area. The pixel size was calibrated to an accuracy of approximately 0.1% by measuring an aluminum rod of known diameter. The CT data software Analyze (Mayo Clinic, Rochester, MI) was used to process the serial CT cross-sectional images. First, 3-dimensional surface–rendered images of the osseous elements were obtained by appropriate thresholding. The falciform bone was then segmented out to avoid obstructing the visualization of the sesamoid area (Yasuda and Tsunetsugu 1996). Finally, the orientation and direction of the views of the specimens were assessed and standardized visually so that the long axis of the 2 sesamoid bones lay horizontal. By using the standardized and reformatted data sets, we obtained serial slices from the distal to the proximal side of the sesamoid bones.
Other Methods
Total RNAs were prepared from the E12.5 mouse embryos by using TRIZOL reagent (Invitrogen, Carlsbad, CA) according to the manufacturer's instructions. To confirm the presence of a junction between exons 1 and 2 of Hoxd-13, reverse transcriptase (RT)–PCR was performed using Super Script First-Strand Synthesis System for RT–PCR (Invitrogen) with 5'-TCCACGTTCGCTTACCCAGG-3' and 5'-GGTTTAAAGCCACATCTCCT-3' as the primers. Full-length Hoxd-13 cDNA was cloned into the mammalian expression vector pIRES-hrGFP-2a (Invitrogen). The constructs encoded a hemagglutinin-tagged Hoxd-13 protein, and they simultaneously expressed bicistronic green fluorescent protein, which gets distributed throughout the cytoplasm and nucleus. The vectors were transfected into NIH3T3 cells by using FuGENE 6 (Roche, Mannheim, Germany) according to the manufacturer's instructions. At 48 h after transfection, the cells were analyzed using the standard immunofluorescence staining method with Alexa 546–conjugated goat antimouse IgG (Molecular Probes Inc., Eugene, OR) as the secondary antibody. Whole-mount in situ hybridization was performed by the standard method (Nagy 2002). The probe used was a 1,318-bp PvuII-HindIII fragment including the 3'-terminal region of mouse Hoxd-13, as described previously (Dollé et al. 1991). The probe was prepared by in vitro transcription using a DIG RNA labeling kit (Roche).
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Results |
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Figure 1 shows the amino acid sequence alignment of the Hoxd-13 gene in vertebrates. The species employed were human (Homo sapiens: NM_000523 [GenBank] ), chimpanzee (Pan troglodytes: ENSPTRG00000012664), mouse (Mus musculus: NM_008275 [GenBank] ), rat (Rattus norvegicus: ENSRNOG00000001588), bat (Carollia perspicillata: AY744676 [GenBank] ), chicken (Gallus gallus: NM_205434 [GenBank] ), newt (Pleurodeles waltl: AY383548 [GenBank] ), frog (Xenopus laevis: AY167742 [GenBank] and Xenopus tropicalis: ENSXETP00000016487), shark (Heterodontus francisci: AF224263 [GenBank] ), and zebrafish (Danio rerio: NM_131169 [GenBank] ). The sequences were initially aligned using multiple sequence alignment programs ClustalX and ClustalW (Thompson et al. 1997
) and were further visually adjusted. Sequence comparison disclosed a remarkable feature that is peculiar to mammals. Polyalanine and polyserine tracts were present in the mammalian Hoxd-13 genes, whereas all of these repeats were absent in the nonamniote homologues. No polymorphisms in repeat length were observed among 132 alleles of healthy humans (Muragaki et al. 1996; Goodman et al. 1997). Among these tracts, the polyalanine tract that causes synpolydactyly and comprises 15 alanine residues in humans was the most conserved in length among mammals. Chickens showed an intermediate feature between mammals and nonamniotes. This implies that this polyalanine was acquired before the divergence of amniotes during vertebrate evolution. To investigate the functional implications of the polyalanine tracts, we generate a mouse Hoxd-13 construct that lacked the 15-residue polyalanine tract–coding region, and by using homologous recombination, we replaced a wild-type mouse Hoxd-13 gene with the construct as shown in figure 2.
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According to Dollé et al. (1993)
, the first finger of Hoxd-13 knockout (Hoxd-13st/Hoxd-13st) mice is completely fused and has no joints. To investigate morphological changes caused by loss of the polyalanine tract in the Hoxd-13
A knock-in mouse, we analyzed the skeletal form of the forelimb and hindlimb autopods in detail. The first finger has small bones known as the sesamoid bones between the proximal phalange and the metacarpal. These bones are present in the tendon or around a joint capsule and are considered to function in reducing friction (Gibeault et al. 1989). We observed a variation in the number of sesamoid bones in the first finger of the forelimb, that is, there was either a single or 2 sesamoid bones (see fig. 3). Micro-CT analysis revealed that the single-type bone contained 2 cavities (see fig. 4). Because a single bone usually contains a single cavity, this finding implies that the single-type sesamoid bone originally comprised 2 bones; in other words, it implies the occurrence of fusion during development. We designated the single- and 2-type sesamoid bones as the "fused" and "separated" types, respectively. In wild-type mice, the separated and the fused types were observed at frequencies of approximately two- and one-thirds, respectively. On the other hand, the fused type predominated in the Hoxd-13A homozygous mice (see table 1). Fisher's exact test revealed the presence of a statistically significant difference between the wild-type and Hoxd-13A homozygous mice (P < 0.001). A significant difference was not observed between the wild-type and Hoxd-13A heterozygous mice, but there is a clear regressive tendency toward decreasing the number of the sesamoid bones with increasing the number of the mutant Hoxd-13A allele (P < 0.001, regression analysis). The average numbers of the sesamoid bones per limb were 1.71, 1.42, and 1.20 for the wild-type, the Hoxd-13A heterozygous, and the Hoxd-13A homozygous mice, respectively, and there was a severe increase in the appearance frequency of the limb with a fused sesamoid bone (P < 1 x 10–6, regression analysis).
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The mouse Hoxd-13 gene comprises 2 exons. The normal splicing pattern of the mutant Hoxd-13
A homozygous mouse was verified by RT–PCR and direct sequencing using the total RNA prepared from E12.5 mouse embryos. It is known that polyalanine expansion causes the cytoplasmic aggregation of the mutant Hoxd-13 protein (Albrecht et al. 2004). We then examined the intracellular localization of the mutant Hoxd-13A protein by cell culture assay and immunostaining. Similar to the wild-type Hoxd-13, the mutant Hoxd-13A protein was located in the nucleus and did not aggregate in the cytoplasm, as shown in figure 5A. Whole-mount in situ hybridization also revealed that the expression pattern of the mutant Hoxd-13A allele was similar to that of the wild-type allele (see fig. 5B). These results indicate that the increased frequency of occurrence of the fused sesamoid bone in the Hoxd-13A mouse was dependent on the lack of the polyalanine tract in the Hoxd-13 gene. The Hoxd-13 knockout (Hoxd-13st/Hoxd-13st) and spdh mutant (Hoxd-13spdh/Hoxd-13spdh) mice showed male sterility and characteristic disorders of the male sex accessory organs, including diminished mesenchymal folding in the seminal vesicle and the lack of a preputial gland (Dollé et al. 1993, Johnson et al. 1998), but we did not observe any obvious differences in the sex accessory organs between wild-type mice and Hoxd-13A/Hoxd-13A mice (data not shown).
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Discussion |
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We presented a mouse model to investigate the types of changes that occurred at the organismal level due to the acquisition of taxon-specific components during evolution. In this study, we attempted to trace back to the mammalian ancestor whose Hoxd-13 lacked the homopolymeric amino acid repeats, which are present in the extant mammals. Homopolymeric amino acid repeats are observed in many eukaryotic proteins. Most of these proteins are transcription factors (Sumiyama et al. 1996
; Nakachi et al. 1997; Alba and Guigo 2004; Brown LY and Brown SA 2004; Hancock and Simon 2005; O'Dushlaine et al. 2005), and the repeats are present in the transactivation domain's domain (Mermod et al. 1989; Mitchell and Tjian 1989; Licht et al. 1990; Tanaka et al. 1994; Catron et al. 1995; Hanna-Rose and Hansen 1996; Galant and Carroll 2002). A transcription factor that is artificially fused with the homopolymeric amino acid repeats significantly modulates its transcriptional activation and intracellular localization (Gerber et al. 1994; Oma et al. 2004). Some homopolymeric amino acid repeats play a role in protein–protein interactions (Faux et al. 2005); some are involved in protein–RNA interactions, depending on the lengths of the repeats (Yue et al. 2001). In addition, it has recently been reported that a polymorphism in the length of the polyaspartic acid tract in asporin is correlated to osteoarthritis (Kizawa et al. 2005).
In Drosophila, the Ultrabithorax protein possesses a QA motif containing a polyalanine tract, and the QA motif acquired during arthropod evolution is observed only in insects (Galant and Carroll 2002). In mammals, it is well known that aberrant expansion of homopolymeric amino acid repeats causes severe diseases (Gatchel and Zoghbi 2005). Recently, a correlation has been proposed between facial morphology and the length of the polyalanine tract in dogs (Fondon and Garner 2004); however, little is known about the normal function of the homopolymeric amino acid repeats at the organismal level. A mutant fly that artificially lacks a QA motif containing a polyalanine tract shows abnormal patterning of bristles and trichomes (Hittinger et al. 2005), and a chicken Hoxd-13 mutant (N-terminal truncated mutant) results in shortening of the long bones (Goff and Tabin 1997). However, one cannot conclude that these abnormalities are due to lack of the polyalanine tracts because the mutants are deficient in the other parts of the respective genes in addition to lack of the polyalanine tracts. It is, therefore, not possible to exclude the possibility that other sequences (elements) contribute to these abnormalities. We here examined the role of a polyalanine tract alone, employing knock-in mouse technique. To our knowledge, the present study is the first report that provides direct evidence for the contribution of homopolymeric amino acid repeats to the change that occurs at the organismal level. In particular, the results obtained are noteworthy with regard to the influence of the presence/absence of taxon-specific, that is, evolutionarily unconserved, homopolymeric amino acid repeats on morphogenesis. The present results support our previous hypothesis that taxon/species-specific homopolymeric amino acid repeats play an important role in phenotypic diversification during evolution (Nakachi et al. 1997).
It has been shown that the polyalanine tracts in the mammalian Hoxd-13 gene are acquired during vertebrate evolution, probably before the divergence of the amniotes. This suggests that the acquisition is related to limb development that is exclusive to terrestrial animals. Although the polyalanine tract of Hoxd-13 led to morphological change in the limbs, its influence was restricted to microchanges, such as that involved in sesamoid bone formation. One explanation for such moderate change is that other polyalanine tracts compensate for the loss of the 15-residue polyalanine tract in the present study. If so, mutant mouse missing all of the amino acid repeats is expected to show more severe changes. An alternative is that many genes are involved in limb formation and the alteration of a single gene is insufficient to trigger evolutionarily crucial changes. Hoxa-13 and Hoxd-11 genes also play important roles in limb formation. Similar to Hoxd-13, taxon-specific polyalanine tracts also exist in mammalian Hoxa-13 and Hoxd-11 (Mortlock et al. 2000; Lavoie et al. 2003). Multiple losses of the taxon-specific polyalanine tracts in each Hox gene should have a profound influence on the morphological diversification of vertebrates, even though the effect of each polyalanine tract is moderate. Further studies will shed light on the general properties of homopolymeric amino acid repeats and their evolutionary implications.
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Acknowledgements |
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This study was supported by grants from the Ministry of Education, Science, Sports, and Culture of Japan. We thank Dr G. Suwa, Ms M. Chubachi, and Mr D. Kubo for micro-CT analysis and Drs M. Taira and M. K. Park for Xenopus and reptile samples, respectively. We also thank Dr L. Wang for critical reading of the manuscript.
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Footnotes |
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Takashi Gojobori, Associate Editor
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