| Human Molecular Genetics | Pages |
A new human homeobox gene OGI2X is a member of the most conserved homeobox gene family and is expressed during heart development in mouse
Introduction
Results
Isolation of OG12X cDNA from the human craniofacial library
Expression of murine Og12x during embryogenesis
Mapping of human OG12X to 3q22-26 and of mouse Og12x to the syntenic region of mouse chromosome 3
Discussion
Materials And Methods
Screening of cDNA libraries
Detection of Og12x expression in mouse embryos
Mapping of human OG12X andmurine Og12x
GenBank accession numbers
Note added in proof
Abbreviations
Acknowledgements
References
A new human homeobox gene OGI2X is a member of the most conserved homeobox gene family and is expressed during heart development in mouse
INTRODUCTION
The homeobox genes have received enormous attention in developmental biology research. This class of transcription factors comprises key regulators of embryonic development in organisms as diverse as humans and flies. They are thought to be involved in evolution of new regulatory pathways, giving rise to the development of novel features leading to species diversification (1,2). Duplication of these genes occurring close to the origin and early radiation of vertebrates may have allowed recruitment of duplicate genes for new roles in embryogenesis and played an important role in evolution of the vertebrate body plan (2,3).
Mutations in homeobox genes (encoding homeodomain proteins) have been described in a number of human disorders: PAX2 in a family with optic nerve colobomas, renal anomalies, and vesicoureteral reflux; PAX3 in Waardenburg syndrome; PAX6 in aniridia and Peter's anomaly; MSX1 in familial tooth agenesis; MSX2 in craniosynostosis; HOXD13 in synpolydactyly; EMX2 in schizencephyly; IPF1 in pancreatic agenesis; RIEG1 in Rieger syndrome (4).
The homeodomain (HD) is a 60 amino acid sequence containing a helix-turn-helix motif that recognizes and binds specific DNA sequences. Recent studies have shown that the specificity of binding and the activity of HD proteins is modulated by protein-protein interactions involving other regions of the HD protein besides the HD itself (5-10). We recently reported the positional cloning of a homeobox gene involved in the pathogenesis of Rieger syndrome, RIEG1 (11). By comparing its protein sequence with those in GenBank we identified a 14 amino acid motif within the C-terminal region that is conserved between several HD proteins, some of which have overlapping sites of expression. This motif may represent a domain of protein-protein interaction or be involved directly in DNA binding. In order to identify new genes possessing this motif we screened a human embryonic craniofacial cDNA library with oligoprobes recognizing this region.
A new gene was identified, exhibiting the strongest homology to murine Og12x (formerly OG12; 12) and a recently reported human SHOX/PHOG gene possibly involved in the short stature phenotype of Turner syndrome (13,14). Although it was suggested that murine Og12x is the mouse homolog of human SHOX/PHOG (13,14), we present evidence that the novel human gene reported herein (henceforth OG12X) is the true human homolog of murine Og12x. Human OG12X and murine Og12x are similar in their 5[prime]- and 3[prime]-UTRs and the proteins encoded by these genes are 100% identical. In situ hybridization on mouse embryos ranging from 9 to 16 days post-coitum (pc) demonstrates murine Og12x expression in the heart, otic region, maxillary and mandibular components of the first branchial arch, nasal processes, eyelid, midbrain, medulla oblongata, limbs, dorsal root ganglia and genital tubercle.
OG12X was mapped to human chromosome 3q22-26 and murine Og12x to the syntenic region on mouse chromosome 3. The human genomic region 3q22-26 is known to harbor genes responsible for blepharophimosis (BPES; 15,16) and Cornelia de Lange syndromes (17,18).
BPES was first described by Vignes in 1889 as dysplasia of the eyelids (19). The characteristic features of BPES (blepharophimosis, ptosis and epicanthus inversus) have often been found in association with premature ovarian failure (POF), suggesting that POF is caused by a pleiotropic effect of the same gene (20) or that BPES along with POF represents a contiguous gene syndrome. Other features often associated with BPES are anterior segment eye abnormalities, cleft lip/palate, craniosynostosis, hearing loss (Michels syndrome; 21), and mandibular hypoplasia with aplasia/hypoplasia of the ulna and fibula (Langer type mesomelic dwarfism; 22).
Cornelia de Lange syndrome is recognized on the basis of characteristic facies, with low anterior hairline, maxillary prognathism and long philtrum, in association with pre-natal and post-natal growth retardation, congenital heart defects and, often, limb abnormalities (23,24). Many additional defects have been reported in de Lange patients. Most cases are sporadic. OG12X is a possible candidate for BPES and de Lange syndrome based on the expression of murine Og12x reported in this paper.
RESULTS
Isolation of OG12X cDNA from the human craniofacial library
The 14 amino acid conserved motif was identified by comparison of the RIEG1 protein sequence with other sequences deposited in GenBank, using the BLASTX search engine (11). This motif was found in several HD-containing proteins and three more genes possessing this motif have since been reported (Table 1; 13,25,26).
A human craniofacial embryonic cDNA library was screened with oligoprobes recognizing the region encoding the 14 amino acid motif 5[prime]-AGCCTGGCCAGCCTGAGACTGAAAGC-3[prime] and 5[prime]-CTGAGACTGAAAGCAAAGCAGCA-3[prime]. Ten distinct clones were identified from the 2 × 106 clones examined. These clones were sequenced and analyzed to construct cDNA contigs. Three genes appeared to have been isolated: PRX-2, CART-1 and a novel gene, designated hc5-4, which was then sequenced in both directions.
The hc5-4 cDNA was 2748 bp in length, with a polyadenylation signal found at positions 2728-2732 (Fig. 1). The first methionine associated with the longest open reading frame was found at position 198 of the cDNA. The protein ascribed to the open reading frame consists of 171 amino acid residues and contains a putative HD.
Comparison of the hc5-4 nucleotide and protein sequences with sequences in GenBank identified strong homology with the murine Og12x (formerly OG12) and human SHOX genes (Fig. 2). The most remarkable homology is observed between hc5-4 and the Og12x-b isoform at the protein level; these two proteins are 100% identical. At the nucleotide level hc5-4 is 92% identical to the Og12x-b cDNA in the coding region and an average of 65 and 80% identical in the 5[prime]- and 3[prime]-UTRs respectively. These data strongly suggest that hc5-4 is the human homolog of murine Og12x; therefore, we have named the novel human gene OG12X, inaccordance with guidelines for human gene nomenclature (27). Homology between OG12X and the human SHOX gene and their encoded proteins is also remarkable; 100% identity is seen in the HD, with 98% identity overall between the OG12X protein and the homologous portion of the SHOX protein (Fig. 2), suggesting that these proteins belong to the same family of HD proteins.
Table 1
| Protein | Species | Sequence |
| OG12X | human/mouse | SSIADLRLKAKKHA |
| SHOX | human | ----------R--- |
| Solurshin | human/mouse | --L-S------Q-S |
| Ptx-1/P-OTX | human/mouse | --L-S----S-Q-S |
| Pitx3 | mouse | --L-S------Q-- |
| Prx-2 | mouse/chicken | N---S------EFS |
| Prx-1 | mouse/chicken | N---N------EYS |
| Cart-1 | mouse | ----V--M---E-T |
| al | Drosophila | ----A-----RE-E |
| Drg11 | rat | A-V-A--M--RE-S |
| Chx10 | mouse | N---A--A--QE-S |
| Otp | mouse | T------R--LE-T |
| rax | mouse | ----A------E-I |
| Consensus | SSIASLRLKAKEHS | |
| A T |
Expression of murine Og12x during embryogenesis
Figure
Figure
The mouse Og12x clone was isolated by screening a mouse day 15 embryo cDNA library (Novagene) with a probe containing a portion of the human OG12X cDNA (nt 450-1130). Five distinct clones were isolated from the 1 × 106 clones examined and sequenced. The clone pd15-2, mostly containing the 3[prime]-UTR sequence of the murine Og12x cDNA, was chosen for use in in situ hybridization.
Whole-mount in situ hybridization on 9, 10, 11 and 12 day pc mouse embryos revealed the first notable expression in day 9 pc embryos in the region of the developing heart, which becomes very strong in day 10 pc and is diminished in day 11 and day 12 pc embryos (Fig. 3). In day 9 and day 10 pc embryos the signal seems to be restricted to the sinus venosus region. In the otic region Og12x mRNA seems to be present in the trigeminal (V) ganglion and facio-acoustic (VII-VIII) ganglion complex. The medial nasal processes and forelimb buds also exhibit Og12x expression in day 10 pc embryos. In day 11 pc embryos expression in the medial and lateral nasal process is more distinct, while expression in the otic region is diminished in comparison with day 10. Expression in the forelimbs and hindlimbs is strong at this stage. New sites of expression include the dorsal root ganglia and regions of the diencephalon and mesencephalon. In day 12 pc embryos expression continues in the nasal processes, midbrain region and limbs. In the limbs expression is restricted to the proximal portions. Distinct new expression is seen in the maxillary and mandibular epithelia and adjacent mesenchyme at this stage.
Figure
Hybridization on transverse sections through the head region revealed a strong signal in nasal processes and weak signal in the mandible in day 11 pc embryos and strong signal in the mesenchyme of the maxillary component of the first branchial arch in day 12 pc embryos (data not shown). Hybridization on transverse sections through the limbs revealed a strong signal in the mesenchyme of both forelimb and hindlimb in day 11 and day 12 pc embryos, with the signal being mostly localized in the middle part of the limb, in the regions later to develop into the ulna and radius of the forelimb and fibula and tibia of the hindlimb (Fig. 4). On transverse sections at the level of the forelimb in day 12 pc embryos a signal is also seen in the region of the sinus venosus, the wall of the atrium and the region of the truncus arteriosus (Fig. 4). On sagittal sections of the day 11 pc embryo hybridization signal is seen in the region of the diencephalon and cerebellar primordium of the developing brain, nasal processes, otic region [facio-acoustic (VII-VIII) ganglion complex], dorsal root ganglia and part of the body wall (midgut) overlying the pericardial cavity (Fig. 5). In the day 15 pc embryo a strong signal was localized to the midbrain, part of the medulla oblongata, nasal processes, palate, the mesenchyme surrounding the head of the femur and the genital tubercle. Weak signal is seen in the head muscles and the digits of the hindlimb (Fig. 5). Sections of the head at the eye level of day 16 pc embryos (Fig. 6) revealed a distinct signal in the medulla oblongata, head muscles and the inner layer of the fused eyelids, with the highest level in the region adjacent to the forming conjunctival sac (28).
Figure
Figure
Figure
Mapping of human OG12X to 3q22-26 and of mouse Og12x to the syntenic region of mouse chromosome 3
To pinpoint the locus of OG12X in the human genome the radiation hybrid (RH) mapping panel GeneBridge 4 was typed by PCR with primers specific for the 3[prime]-UTR of the gene. Twenty nine of 93 RH lines were positive for OG12X-specific sequence (retention frequency 31%). OG12X was placed 3.67 cR distal from WI-5784, located in the q22-26 region of human chromosome 3.
A single-strand conformational variant between C57BL/6J and Mus spretus was identified for the 282 bp PCR product amplified with primers specific for the 3[prime]-UTR of Og12x. The Jackson Laboratory interspecific backcross panel (C57BL/6J × M.spretus)F1 × C57BL/6J (BSB) was then used to map Og12x in the mouse genome. Og12x maps to the proximal half of mouse chromosome 3, within the sequence proximal- D3Hun6- 10.64±3.18-Og12x-1.06±1.06-[D3Hun7; D3Hun8; Rp132-ps]- distal. Our data are in agreement with the mapping of Og12x by Ellison et al. (14) in a different (BSS) cross. This portion of mouse chromosome 3 has regions homologous to human chromosomal regions 3q22-26 and 4q32-35. The location of Og12x appears to be within the region syntenic to human 3q25-26, as murine Ptx3 was mapped to the same location (1.45 cM from the marker D3Hun7) and has a human homolog, PTX3, which has been localized to the human 3q25-26 chromosomal region (MGD: Mouse Chromosome 3 Linkage Map at http://www.informatics.jax.org/bin/get_map). Thus human OG12X and mouse Og12x are members of a conserved linkage group.
DISCUSSION
We report here isolation and characterization of a novel human gene, OG12X, a member of the OG12X/SHOX homeobox-containing transcription factor gene family. The human SHOX/PHOG gene was isolated from the pseudoautosomal region (PAR1) deleted in several patients with short stature (SS; 13,14) and was shown to have a mutation co-segregating with idiopathic SS in one family (13). This suggested involvement of SHOX in idiopathic growth retardation and the SS phenotype of Turner syndrome patients. The SHOX/PHOG gene was found to be most closely related to the mouse gene Og12x, encoding a protein of unknown function. It was therefore concluded that Og12x was the mouse homolog of the human SHOX gene (13,14).
We suggest that the new human gene reported in this paper is the true human cognate of mouse Og12x: because it exhibits 65 and 80% identity with Og12x in the 5[prime]- and 3[prime]-UTRs; because the predicted OG12X protein is 100% identical to isoform b of Og12x, while SHOX shares 86% identity with it; because human OG12X and mouse Og12x were mapped to human chromosome 3q22-26 and mouse chromosome 3p respectively, within evolutionarily conserved linkage groups. The extraordinary conservation of this family between human and mouse (OG12X/Og12x) is likely a sign of the evolutionary importance of conservation of protein sequence among these genes. In addition, the strong conservation between different family members (OG12X/SHOX) might be a consequence of their late duplication and correspondingly short divergence time.
OG12X was isolated in a search for genes possessing the conserved 14 amino acid motif originally identified in the C-terminal end of solurshin (encoded by the RIEG1 homeobox gene; 11). This region may be involved in additional DNA binding (outside the HD-DNA interaction) or may be a site of protein-protein interaction, important in the specificity of function of the HD protein (11). Expression of some of the 14 amino acid motif-containing genes seems to overlap in some regions, suggesting that there may be a regional factor shared by those proteins and required for their action. Specifically, expression in the orofacial epithelia and mesenchyme, brain, nasal cavity, head muscles, the heart and limb mesenchyme overlaps with the expression domains of Pitx and prx genes, which also possess the 14 amino acid motif. Furukawa et al. recently reported a new gene, rax, containing this 14 amino acid motif, called the OAR domain by this group, and suggested its possible role in transactivation (25). Further experiments will provide more insights into the possible function of this conserved domain.
In situ hybridization on whole-mount and sectioned mouse embryos ranging from day 9 to day 16 pc revealed an extremely dynamic expression pattern for Og12x, with the earliest expression seen in the developing heart. Expression of Og12x during early heart development seemed to be restricted to the regions forming inflow and outflow tract systems. The role of Og12X in heart development and its possible interaction with the Nkx-2-family HD proteins, shown to be highly important for regulation of the cardiac gene program (29,30), can now be investigated.
Og12x was found to be strongly expressed in the mesenchyme of developing limbs. The expression tends to the medial part of the limbs, as is particularly evident in day 12 pc embryos, the regions presumably later to give rise to the ulna/radius and fibula/tibia bones of the forelimbs and hindlimbs respectively. Other homeobox genes shown to be important for development of the ulna and radius include Hox genes hoxa-11 and hoxd-11, as these structures were almost entirely eliminated in double mutants for these genes (31). Hoxd-13 misexpression in the hindlimb results in a shortening of the long bones, including the femur, the tibia, the fibula and the tarsometatarsals (32). Mutations in the alanine repeat region in the N-terminus of Hoxd-13 have recently been implicated in human synpolydactyly (33).
We mapped the OG12X gene to 3q22-26. This region contains the gene for blepharophimosis syndrome (BPES) and Cornelia de Lange syndrome. Cornelia de Lange syndrome also has a phenotypic equivalent involved in a 3q duplication. Blepharophimosis syndrome is characterized by eye features such as blepharophimosis (dysplasia of the eye lid), ptosis and epicanthus inversus (19). Frequently associated features include female infertility, due to atrophic ovaries or premature ovarian failure (POF) in some cases (20,34,35), mandibular hypoplasia with aplasia/hypoplasia of the ulna and fibula (Langer type mesomelic dwarfism; 22), anterior segment eye abnormalities, cleft lip/palate, craniosynostosis, hearing loss (Michels syndrome; 21) and microcephaly (36). Some authors have proposed that BPES with additional features might represent a contiguous gene syndrome or reflect a pleiotropic effect of the BPES gene. Only BPES with POF was shown to be linked to the BPES locus, which led to separate designations of blepharophimosis syndrome type I (BPES itself) and type II (BPES with POF; 23). The expression pattern of Og12x suggests a role for human OG12X in BPES and associated abnormalities: Og12x is expressed during eyelid formation at the most critical stage of its development (BPES type I), in the condensing limb mesenchyme and the maxillary-mandibular component of the first branchial arch (Langer type mesomelic dwarfism), the eyelid at the closure stage (eyelid closure leads to differentiation of the cornea, abnormal development of which is associated with various anterior eye defects), palate and otic region (Michels syndrome).
Cornelia de Lange syndrome is characterized by multiple congenital malformations and is recognized primarily on the basis of characteristic facies, with low anterior hairline, synophrys, maxillary prognathism, long philtrum and a thin upper lip with a crescent-shaped mouth and pre-natal and post-natal growth retardation (17,23,24). Associated eye features include ptosis, nystagmus and Peter's anomaly (37). Limb defects have been frequently described, with absence of the ulna and tibia in some cases (38). Congenital heart malformations have been reported in ~30% of patients (39) and include ventricular septal defects, pulmonic stenosis and right-sided obstructive lesions. Most cases are sporadic, although some involve a 3q translocation (24). OG12X could thus represent a candidate for Cornelia de Lange syndrome on the basis of expression of its murine homolog.
Duplication of 3q is also described in the literature as a dup(3q) syndrome, which overlaps significantly in phenotypic expression with de Lange syndrome (40). A clinical comparison of these two syndromes by Breslau (41) demonstrated that convulsions, eye, palate, renal and cardiac anomalies and club foot are more common for the dup(3q) syndrome, whereas small hands and feet, limb reduction anomalies, synophrys, low birth weight and growth retardation are more frequent in de Lange syndrome.
The role that OG12X may play in abnormal development leading to BPES, de Lange or dup(3q) syndromes must be evaluated further. Mapping of associated translocation breakpoints and deletions with respect to OG12X and mutation studies will certainly provide some clues. Creation of mouse null mutants and overexpression transgenic lines for Og12x might be of particular help in this case because of the intriguing overlap between the phenotypes.
MATERIALS AND METHODS
Screening of cDNA libraries
Human embryonic craniofacial and mouse cDNA libraries [embryonic carcinoma (Stratagene) and day 15 embryo (Novagene)] were screened with oligoprobes recognizing the region encoding the 14 amino acid motif 5[prime]-AGCCTGGCCAGCCTGAGACTGAAAGC-3[prime] and 5[prime]-CTGAGACTGAAAGCAAAGCAGCA-3[prime], labeled during a kinase reaction. Hybridization was carried out in standard hybridization buffer at 50°C for 4 h, followed by several washes at room temperature and one 15 min wash at 55°C in 2× SSC. Plasmids from positive plaques were isolated from their Uni-Zap XR or [lambda]EXloxR hosts by in vivo excision with R408 helper phage as described by the manufacturer. Bluescript plasmids containing cDNA inserts were sequenced and analyzed using the BLASTN and GRAIL search engines.
Detection of Og12x expression in mouse embryos
A 0.8 kb fragment spanning most of the 3[prime]-UTR of Og12x cDNA was used to create probes for in situ hybridization. From linearized cDNA 35S- or digoxigenin-labeled RNA probes were synthesized using either T3 or T7 RNA polymerase. NIH Swiss mice from Harlan (Indianapolis, IN), staged according to Theiler (42), were used.
Embryonic mice for radioactive in situ hybridization on sections were fixed overnight at 4°C in 4% paraformaldehyde in PBS, dehydrated, cleared in Histosol (National Diagnostics) and embedded in Paraplast Plus (Oxford). Seven micron sections were cut and mounted on Superfrost-plus slides (Fisher) with DEPC-treated water, dried overnight at 40°C and then stored at room temperature. Before use the slides were baked at 60°C overnight and then processed for in situ hybridization as described by Sassoon and Rosenthal (43). Slides were hybridized overnight at 50°C, washed in 5× SSC at 50°C to remove coverslips and then washed in 2× SSC, 50% formamide at 60°C. Autoradiography was with Kodak NTB-2 emulsion. Embryonic mice for whole-mount in situ hybridization were fixed and processed according to a modification of the method of Harland (44).
Mapping of human OG12X andmurine Og12x
The radiation hybrid panel GeneBridge 4 was obtained from Research Genetics and typed by PCR with primers specific forthe 3[prime]-UTR of OG12X (5[prime]-ttgtagctttgcggtgagccaaact-3[prime], forward, and 5[prime]-tcgcatcttggactcggaaa-3[prime], reverse, product size 198 bp). The products of each of 82 reactions were electrophoresed on a 2% agarose gel and inspected for the presence of a fragment of the expected size. The results were submitted to the Whitehead Institute/MIT Center for Genome Research at web address http://www.genome.wi.mit.edu/cgi-bin/contig/rhmapper.pl.
The BSB interspecific backcross panel was obtained from the Jackson Laboratory (Bar Harbor, ME). Each panel contains 94 backcross animals plus parental controls (45). Complete haplotype data for these crosses are available at http://www.jax.org/resources/documents/cmdata. A 330 bp fragment of Og12x sequence was amplified with the primers 5[prime]-tgtggttcaagaaccggc-3[prime], forward, and 5[prime]-ttgaccgagttgaaggcgaa-3[prime], reverse. Amplification was carried out in a PCR thermocycler (Perkin-Elmer Cetus), with a single 4 min 94°C stage followed by 30 cycles comprising three 30 s steps at 94, 55 and 72°C each, in a 10 µl total volume of 1 µl Boehringer PCR buffer, 2.5 pmol each primer, 2 mM each dNTP and 0.25 U Taq polymerase (Boehringer). PCR products were heated for 4 min at 95°C and electrophoresed for 4 h at 20 W through a fan-cooled gel composed of 3.3 ml 10× TBE, 1.37 ml glycerol, 13.75 ml MDE mix (from FMC), 36.6 ml water, 220 µl 10% APS and 22 µl TEMED. After silver staining the gels were visually inspected and genotyped. Genotypes were submitted to the Jackson Laboratory for interpretation.
GenBank accession numbers
The human sequence of OG12X and partial mouse sequence of Og12x are available from GenBank as accession nos AF023203 and AF022654 respectively.
Note added in proof
The expression pattern of a rat Og12 gene (named Prx3) was recently described by Van Schaick et al. (46).
ABBREVIATIONS
bp, base pair(s); BPES, blepharophimosis, ptosis and epicantus inversus syndrome; HD, homeodomain; pc, post-coital; PCR, polymerase chain reaction; POF, premature ovarian failure.
ACKNOWLEDGEMENTS
The authors would like to thank Bonnie Ludwig for DNA sequencing and Nancy Newkirk for administrative help. This work was supported by grant DE-08559, CARC grant DE-09170 and DERC grant DK-25295 from the US National Institutes of Health.
REFERENCES
*To whom correspondence should be addressed at: Department of Pediatrics, The University of Iowa, 200 Hawkins Drive, W229-1 GH, Iowa City, IA 52242-1083, USA. Tel: +1 319 335 6897; Fax: +1 319 335 6970; Email: jeff-murray@uiowa.edu
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