Chordin

Chordin (from Greek χορδή, string, catgut) or CHRD is a protein with a prominent role in dorsal–ventral patterning during vertebrate early embyronic development .[1] Chordin is encoded by the chrd gene.[2]

CHRD domain
Identifiers
Symbol	CHRD
Pfam	PF07452
InterPro	IPR010895
SMART	SM00754
PROSITE	PS50933
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

chordin
Identifiers
Symbol	CHRD
NCBI gene	8646
HGNC	1949
OMIM	603475
RefSeq	NM_003741
UniProt	Q9H2X0
Other data
Locus	Chr. 3 q27

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 that dorsalizes early vertebrate embryonic tissues.[3] 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[4] mRNA 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, the notochord, 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 structure resembles a horseshoe.[5][6] A characteristic structural feature of chordin is the presence of four cysteine-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.[7] There are five named isoforms of this protein that are produced by alternative splicing.[8]

Gene Structure

The CHRD gene is 23 exons long and has a length of 11.5 kb and is localized at 3q27.[1][9] The THPO (Thrombopoietin) gene is located in the same single cosmid clone along with the eukaryotic translation initiation factor-4-gamma gene (EIF4G1).[2]

Function

Chordin dorsalizes the developing embryo by binding ventralizing TGFβ proteins such as bone morphogenetic proteins (BMP) through its four cytosine rich regions.[7][9] 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.[10] Chordin specifically inhibits BMP-2,-4,-7.[6] 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.[7]

Experiments with zebrafish showed that a chordin gene mutation can lead to less neural and dorsal tissue. Target gene deletions of chordin, follistatin, 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.[11] This is significant because when only noggin is deficient there are mild defects but the head still forms.[12] Noggin has been shown to have overlap at the midgastrula in its expression with chordin.[13] Further experiments testing the role of both noggin and chordin showed that these two proteins are essential for mesodermal 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.[13]

Chordin mRNA in mice are expressed early on during the anterior primitive streak. It is expressed in the anterior cells of Koller's sickle, which form the anterior cells of the primitive streak, a key structure through which gastrulation occurs.[14] 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.[13] 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 embyros 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.[1]

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.[13] In developing mice that are deficient in both chordin and noggin, the head is nearly absent. Chordin is also involved in avian gastrulation and may also play a role in organogenesis.

References

1. Scott IC, Blitz IL, Pappano WN, Imamura Y, Clark TG, Steiglitz BM, et al. (September 1999). "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". Developmental Biology. 213 (2): 283–300. doi:10.1006/dbio.1999.9383. PMID 10479448.
2. Smith M, Herrell S, Lusher M, Lako L, Simpson C, Wiestner A, et al. (1999). "Genomic organisation of the human chordin gene and mutation screening of candidate Cornelia de Lange syndrome genes". Human Genetics. 105 (1–2): 104–11. doi:10.1007/s004390051070. PMID 10480362.
3. Sasai Y, Lu B, Steinbeisser H, Geissert D, Gont LK, De Robertis EM (December 1994). "Xenopus chordin: a novel dorsalizing factor activated by organizer-specific homeobox genes". Cell. 79 (5): 779–90. doi:10.1016/0092-8674(94)90068-X. PMC 3082463. PMID 8001117.
4. https://www.uniprot.org/uniprot/B7ZPL0
5. Larraín J, Bachiller D, Lu B, Agius E, Piccolo S, De Robertis EM (February 2000). "BMP-binding modules in chordin: a model for signalling regulation in the extracellular space". Development. 127 (4): 821–30. PMC 2280033. PMID 10648240.
6. Troilo H, Barrett AL, Wohl AP, Jowitt TA, Collins RF, Bayley CP, et al. (October 2015). "The role of chordin fragments generated by partial tolloid cleavage in regulating BMP activity". Biochemical Society Transactions. 43 (5): 795–800. doi:10.1042/BST20150071. PMC 4613500. PMID 26517884.
7. Grunz H (2013-03-09). The Vertebrate Organizer. Springer Science & Business Media. ISBN 978-3-662-10416-3.
8. Millet C, Lemaire P, Orsetti B, Guglielmi P, François V (August 2001). "The human chordin gene encodes several differentially expressed spliced variants with distinct BMP opposing activities". Mechanisms of Development. 106 (1–2): 85–96. doi:10.1016/S0925-4773(01)00423-3. PMID 11472837.
9. Pappano WN, Scott IC, Clark TG, Eddy RL, Shows TB, Greenspan DS (September 1998). "Coding sequence and expression patterns of mouse chordin and mapping of the cognate mouse chrd and human CHRD genes". Genomics. 52 (2): 236–9. doi:10.1006/geno.1998.5474. PMID 9782094.
10. Plouhinec JL, Zakin L, Moriyama Y, De Robertis EM (December 2013). "Chordin forms a self-organizing morphogen gradient in the extracellular space between ectoderm and mesoderm in the Xenopus embryo". Proceedings of the National Academy of Sciences of the United States of America. 110 (51): 20372–9. Bibcode:2013PNAS..11020372P. doi:10.1073/pnas.1319745110. PMC 3870759. PMID 24284174.
11. Sanes DH, Reh TA, Harris WA (2005-11-02). Development of the Nervous System. Elsevier. ISBN 978-0-08-047249-2.
12. Harris WA, Sanes DH, Reh TA (2011). Development of the Nervous System (Third ed.). Boston: Academic Press. p. 15. ISBN 978-0-12-374539-2.
13. Bachiller D, Klingensmith J, Kemp C, Belo JA, Anderson RM, May SR, et al. (February 2000). "The organizer factors Chordin and Noggin are required for mouse forebrain development". Nature. 403 (6770): 658–61. Bibcode:2000Natur.403..658B. doi:10.1038/35001072. PMID 10688202.
14. Vasiev B, Balter A, Chaplain M, Glazier JA, Weijer CJ (May 2010). "Modeling gastrulation in the chick embryo: formation of the primitive streak". PLOS One. 5 (5): e10571. Bibcode:2010PLoSO...510571V. doi:10.1371/journal.pone.0010571. PMC 2868022. PMID 20485500.