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Chordin (from Greek χορδή, string, catgut) is a protein with a prominent role in dorsal–ventral patterning during early embryonic development. In humans it is encoded for by the ''CHRD'' gene.


History

Chordin was originally identified in the African clawed frog (''Xenopus laevis'') in the laboratory of Edward M. De Robertis as a key developmental
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that dorsalizes early
vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with ...
embryonic tissues. It was first hypothesized that chordin plays a role in the dorsal homeobox genes in Spemann's organizer. The chordin gene was discovered through its activation following use of gsc ( goosecoid) and Xnot
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
injections. The discoverers of chordin concluded that it is expressed in embryo regions where gsc and Xnot were also expressed, which included the
prechordal plate In the development of vertebrate animals, the prechordal plate is a "uniquely thickened portion" of the endoderm that is in contact with ectoderm immediately rostral to the cephalic tip of the notochord. It is the most likely origin of the rost ...
, the
notochord In anatomy, the notochord is a flexible rod which is similar in structure to the stiffer cartilage. If a species has a notochord at any stage of its life cycle (along with 4 other features), it is, by definition, a chordate. The notochord consi ...
, and the chordoneural hinge. The expression of the gene in these regions led to the name chordin. Initial functions of chordin were thought to include recruitment of neighboring cells to assist in the forming of the axis along with mediating cell interactions for organization of tail, head, and body regions.


Protein Structure

Chordin is a 941 amino-acids long protein, whose three-dimensional
transmission electron microscopy Transmission electron microscopy (TEM) is a microscopy technique in which a beam of electrons is transmitted through a specimen to form an image. The specimen is most often an ultrathin section less than 100 nm thick or a suspension on a ...
structure resembles a horseshoe. A characteristic structural feature of chordin is the presence of four
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, some ...
-rich repeats, which are 58–75 residues long, each containing 10 cysteines with characteristic spacings. These repeats are homologous with domains in a number of extracellular matrix proteins, including von Willebrand factor. There are five named
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some is ...
s of this protein that are produced by
alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be i ...
.


Gene structure

''CHRD'' is 23 exons long and has a length of 11.5 kb and is localized at 3q27. The ''THPO'' ( thrombopoietin) gene is located in the same single cosmid clone along with the eukaryotic translation initiation factor-4-gamma gene (EIF4G1).


Function

Chordin dorsalizes the developing
embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
by binding ventralizing TGFβ proteins such as
bone morphogenetic protein Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens. Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of ...
s (BMP) through its four cytosine rich regions. Chordin blocks BMP signaling by preventing BMP from interacting with cell surface receptors, which inhibits the formation of epidermis and promoting the formation of neural tissue. Chordin specifically inhibits BMP-2,-4,-7. Chordin function is improved by a few co-factors that include the Twisted Gastrulation gene (Tsg) and the zinc metalloprotease. Tsg improves the ability of Chordin to become a BMP antagonist. Zinc metalloprotease functions by cleaving chordin allows for improved signaling with BMP in complexes that were inactive. This occurs by improving Chordin's substrate ability in cleavage reactions and by releasing BMP from chordin products. Experiments with zebrafish showed that a chordin gene mutation can lead to less neural and dorsal tissue. Target gene deletions of chordin,
follistatin Follistatin also known as activin-binding protein is a protein that in humans is encoded by the ''FST'' gene. Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals. Its primary function is the binding ...
, and noggin in mice were shown to also have effects on neural induction, while deletion of both chordin and noggin showed more severe effects on neural development. The phenotype for this type of deletion showed almost full headlessness. This is significant because when only noggin is deficient there are mild defects but the head still forms. Noggin has been shown to have overlap at the midgastrula in its expression with chordin. Further experiments testing the role of both noggin and chordin showed that these two proteins are essential for
mesoderm The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical Emb ...
al development and anterior pattern elaboration. However, noggin and chordin were not shown to play a significant role in the development of the anterior visceral endoderm. Chordin mRNA in mice are expressed early on during the anterior primitive streak. In the chick embryo it is expressed in the anterior cells of Koller's sickle, which form the anterior cells of the
primitive streak The primitive streak is a structure that forms in the early embryo in amniotes. In amphibians the equivalent structure is the blastopore. During early embryonic development, the embryonic disc becomes oval shaped, and then pear-shaped with the br ...
, a key structure through which gastrulation occurs. As the streak evolves to a node and axial mesoderm, the chordin mRNA is still expressed. This evidence suggests a patterning role of chordin during the early embryo stages. When chordin was inactivated, animals may initially appear to have normal development, but later on issues manifest in the inner and outer ear along with pharyngeal and cardiovascular abnormalities. Experiments with Xenopus embryos showed that overexpression of BMP1 and TLL1 can be used to counteract chordin's dorsalization functions. This finding suggests that the major chordin antagonist is BMP1. In mice, chordin is expressed in the node but not in the anterior visceral endoderm. It has been found to be required for forebrain development. In developing mice that are deficient in both chordin and noggin, the head is nearly absent. Chordin is also involved in avian
gastrulation Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals the blastocyst is reorganized into a multilayered structure known as the gastrula. ...
and may also play a role in organogenesis.


References

{{TGFβ receptor superfamily modulators Proteins Vertebrate developmental biology Von Willebrand factor type C domain CHRD domain