Secreted bone morphogenetic protein antagonists of the Chordin family

Abstract

Chordin, Chordin-like 1, and Chordin-like 2 are secreted bone morphogenetic protein (BMP) antagonists with highly conserved Chordin-like cysteine-rich domains. Recently, Brorin and Brorin-like have been identified as new Chordin-like BMP antagonists. A Chordin ortholog, Short gastrulation, has been identified in Drosophila, a protostome, but not other orthologs. By contrast, Chordin, Chordin-like 1, and Chordin-like 2 have been identified in Ciona intestinalis, the closest living relatives of the vertebrates, but Brorin and Brorin-like have not. However, all these genes have been identified in most vertebrates. These results indicate that Chordin, Chordin-like 1, and Chordin-like 2 were generated early in the metazoan lineage. Later on, Brorin and Brorin-like were potentially generated by a genome duplication event in early vertebrate evolution. All four cysteine-rich domains of Chordin are essential for the regulation of its action. However, Chordin-like 1, Chordin-like 2, Brorin, and Brorin-like contain only two or three cysteine-rich domains. Although their mechanisms of action remain unclear, they might be distinct from that of Chordin. The expression profiles of these genes in mice and zebrafish indicate unique roles at embryonic and postnatal stages. Mutant/knockdown mouse and zebrafish phenotypes indicate roles in morphogenesis during gastrulation, dorsoventral axis formation, ear, pharyngeal, and neural development, and venous and arterial patterning. Aberrant Chordin expression might result in hereditary diseases and cancer. In addition, altered serum Chordin and Chordin-like 1 levels are also observed in non-hereditary diseases. Together, these results indicate pathophysiological roles.