HGNC Approved Gene Symbol: CHRD
Cytogenetic location: 3q27.1 Genomic coordinates (GRCh38) : 3:184,380,054-184,390,739 (from NCBI)
Chordin is a key developmental protein that dorsalizes early vertebrate embryonic tissues by binding to ventralizing TGF-beta (e.g., 190180)-like bone morphogenetic proteins (BMPs; see 112264) and sequestering them in latent complexes (Scott et al., 1999).
Pappano et al. (1998) searched the sequence databases for mammalian chordin sequences and identified ESTs encoding the C-terminal regions of human CHRD and mouse Chrd. They determined the full-length cDNA sequence for mouse Chrd, which predicts a 948-amino acid protein containing 4 internal cysteine-rich repeats and 4 potential N-glycosylation sites. Northern blot analysis detected high levels of a 3.7-kb Chrd transcript in 7-day postcoitum mouse embryos; its level decreased at later developmental stages and in adult tissues. Dot blot analysis of mRNA expression in human adult and fetal tissues showed that CHRD is expressed at the highest level in liver.
Smith et al. (1999) cloned and sequenced a human CHRD cDNA, which encodes a 954-amino acid protein that has 86% sequence identity with the mouse protein.
Chordin dorsalizes early vertebrate embryonic tissues by binding to bone morphogenetic proteins and sequestering them in latent complexes. Scott et al. (1999) showed that BMP1 (112264) and TLL1 (606742) counteracted the dorsalizing effects of chordin upon overexpression in Xenopus embryos. They suggested that BMP1 is the major chordin antagonist in early mammalian embryogenesis and in pre- and postnatal skeletogenesis.
Zhang et al. (2007) found that full-length mouse chordin bound BMP2 (112261) and BMP7 (112267) with similar affinity. Coimmunoprecipitation analysis with mutated chordin proteins showed that BMP2 preferentially bound cysteine-rich domains 1 and 3, which Zhang et al. (2007) called VWC1 and VWC3, of chordin. BMP7 preferentially bound VWC1 and VWC4 of chordin. Chordin bound primarily to the knuckle epitope of Bmp2. Chordin completely prevented binding of Bmp2 to both type I (see BMPR1A; 601299) and type II (BMPR2; 600799) receptors.
Collart et al. (2005) showed that inhibition of Smicl downregulated expression of chordin (CHRD; 603475) and resulted in gastrulation defects in Xenopus. Smicl was required for direct induction of chordin by Xlim1 in Xenopus. Immunoprecipitation analysis showed that Xlim1 was present in a complex with Smad3 (603109) and Smicl. Pull-down assays demonstrated that Xlim1 bound 2 putative Xlim1-binding sites in the chordin promoter.
Smith et al. (1999) determined that the CHRD gene has 23 exons spanning 11.5 kb.
Pappano et al. (1998) localized the human CHRD gene to 3q27 by radiation hybrid mapping and the mouse Chrd gene to proximal chromosome 16 using interspecific backcrosses.
Smith et al. (1999) showed that the CHRD gene and the thrombopoietin gene (THPO; 600044) are located within a single cosmid clone; the 2 genes occupy a total of 21 kb and are transcribed from opposite strands using promoters separated by less than 2 kb. Smith et al. (1999) also showed that the human voltage-gated chloride-channel gene CLCN2 (600570) is located downstream of THPO but in the same transcriptional orientation. In addition, they had evidence that the eukaryotic translation initiation factor-4-gamma gene (EIF4G1; 600495) is located in the same region.
Smith et al. (1999) considered that the CHRD gene and the chordin-regulating goosecoid gene (GSC; 138890) could be candidate genes for Cornelia de Lange syndrome (CDLS; 122470), which had been mapped to 3q. The GSC gene had been detected in close proximity to a 14q32 breakpoint detected in a CDLS patient with a balanced de novo translocation (Wilson et al., 1983). Mutation screening failed to identify CDLS patient-specific mutations in CHRD or GSC. The SOX2 gene (184429), which is located in the same region of chromosome 3, was also screened with negative results.
Mouse chordin mRNA is first expressed in the anterior primitive streak and then in the node and axial mesoendoderm that derives from it, suggesting that chordin may play a role in patterning of the early embryo. However, targeted inactivation of chordin results in stillborn animals that have normal early development and neural induction but display later defects in inner and outer ear development and abnormalities in pharyngeal and cardiovascular organization. Bachiller et al. (2000) demonstrated that at midgastrula, expression of noggin (602991) overlaps that of chordin. Noggin mutants underwent normal gastrulation and anterior central nervous system patterning, although at later stages a number of abnormalities were observed in posterior spinal cord and somites. Bachiller et al. (2000) set up intercrosses between mice compound heterozygous for noggin and chordin mutations, but no double-homozygous mutants were recovered among the neonates. Two chordin/noggin double-null embryos were found among animals dissected close to term. Both were undergoing resorption, but clearly had holoprosencephaly, with a single nasal pit, a cyclopic eye, and agnathia. These malformations, not observed in either mutant on its own, represented the weakest phenotypes found in double-homozygous mice and resembled embryos lacking Sonic hedgehog (SHH; 600725). At embryonic day 12.5, double-mutant embryos were recovered with more severe phenotypes resembling aprosencephaly. In double-mutant embryos dissected at embryonic day 8.5, forebrain reduction was clearly evident. Bachiller et al. (2000) concluded from these data that chordin and noggin are not necessary for establishing the anterior visceral endoderm but are required for subsequent elaboration of anterior pattern. Mesodermal development was also affected, indicated by the lack of shh. Bachiller et al. (2000) suggested that the BMP antagonists chordin and noggin compensate for each other during early mouse development. When both gene products are removed, antero-posterior, dorso-ventral, and left-right patterning are all affected.
Ninomiya et al. (2004) demonstrated that the chordamesoderm of Xenopus possesses an intrinsic antero-posterior (AP) polarity that is necessary for convergent extension, functions in parallel to Wnt (see 164820)/planar cell polarity signaling, as demonstrated by T brachyury (601397) and chordin, and determines the direction of tissue elongation. The mechanism that establishes AP polarity involves activin (147290)-like signaling and directly links mesoderm AP patterning to convergent extension.
Choi and Klingensmith (2009) showed that the fully penetrant Chrd-null mouse phenotype includes dysmorphic ears, absence of the thymus, persistent truncus arteriosus, abnormal aortic arch artery structure, and cleft palate, which is virtually identical to that observed in Tbx1 (602054)-null homozygotes and human individuals with 22q11 deletion syndrome (188400). However, penetrance of the Chrd phenotype is highly dependent on genetic background. In an inbred Chrd-null mouse strain with full penetrance, the authors found that a splice site mutation in the Tbx1 gene was a modifier influencing phenotypic expression, indicating that the fully penetrant Chrd-null phenotype is actually due primarily to a Tbx1 mutation. Chrd-null mice without the Tbx1 mutation had a low penetrance of mandibular hypoplasia, but no cardiac or thoracic organ malformations. The hypomorphic Tbx1 allele resulted in defects resembling 22q11 deletion syndrome, but with a low penetrance of craniofacial malformations, unless Chrd was also mutant. Expression studies suggested that Chrd has a role in promoting Tbx1 expression. The findings suggested that chordin is a modifier of the craniofacial anomalies of Tbx1 mutations, demonstrating the existence of a second-site modifier for a specific subset of the phenotypes associated with 22q11 deletion syndrome.
Bachiller, D., Klingensmith, J., Kemp, C., Belo, J. A., Anderson, R. M., May, S. R., McMahon, J. A., McMahon, A. P., Harland, R. M., Rossant, J., De Robertis, E. M. The organizer factors chordin and noggin are required for mouse forebrain development. Nature 403: 658-661, 2000. [PubMed: 10688202] [Full Text: https://doi.org/10.1038/35001072]
Choi, M., Klingensmith, J. Chordin is a modifier of Tbx1 for the craniofacial malformations of 22q11 deletion syndrome phenotypes in mouse. PLos Genet. 5: e1000395, 2009. Note: Electronic Article. [PubMed: 19247433] [Full Text: https://doi.org/10.1371/journal.pgen.1000395]
Collart, C., Verschueren, K., Rana, A., Smith, J. C., Huylebroeck, D. The novel Smad-interacting protein Smicl regulates chordin expression in the Xenopus embryo. Development 132: 4575-4586, 2005. [PubMed: 16192311] [Full Text: https://doi.org/10.1242/dev.02043]
Ninomiya, H., Elinson, R. P., Winklbauer, R. Antero-posterior tissue polarity links mesoderm convergent extension to axial patterning. Nature 430: 364-367, 2004. [PubMed: 15254540] [Full Text: https://doi.org/10.1038/nature02620]
Pappano, W. N., Scott, I. C., Clark, T. G., Eddy, R. L., Shows, T. B., Greenspan, D. S. Coding sequence and expression patterns of mouse chordin and mapping of the cognate mouse Chrd and human CHRD genes. Genomics 52: 236-239, 1998. [PubMed: 9782094] [Full Text: https://doi.org/10.1006/geno.1998.5474]
Scott, I. C., Blitz, I. L., Pappano, W. N., Imamura, Y., Clark, T. G., Steiglitz, B. M., Thomas, C. L., Maas, S. A., Takahara, K., Cho, K. W. Y., Greenspan, D. S. Mammalian BMP-1/Tolloid-related metalloproteinases, including novel family member mammalian Tolloid-like 2, have differential enzymatic activities and distributions of expression relevant to patterning and skeletogenesis. Dev. Biol. 213: 283-300, 1999. [PubMed: 10479448] [Full Text: https://doi.org/10.1006/dbio.1999.9383]
Smith, M., Herrell, S., Lusher, M., Lako, L., Simpson, C., Wiestner, A., Skoda, R., Ireland, M., Strachan, T. Genomic organisation of the human chordin gene and mutation screening of candidate Cornelia de Lange syndrome genes. Hum. Genet. 105: 104-111, 1999. [PubMed: 10480362] [Full Text: https://doi.org/10.1007/s004399900068]
Wilson, W. G., Kennaugh, J. M., Kugler, J. P., Wyandt, H. E. Reciprocal translocation 14q;21q in a patient with the Brachmann-de Lange syndrome. J. Med. Genet. 20: 469-471, 1983. [PubMed: 6655676] [Full Text: https://doi.org/10.1136/jmg.20.6.469]
Zhang, J.-L., Huang, Y., Qiu, L.-Y., Nickel, J., Sebald, W. von Willebrand factor type C domain-containing proteins regulate bone morphogenetic protein signaling through different recognition mechanisms. J. Biol. Chem. 282: 20002-20014, 2007. [PubMed: 17483092] [Full Text: https://doi.org/10.1074/jbc.M700456200]