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 Chordinlike 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.

CHRDL1 Regulates Stemness in Glioma Stem-Like Cells

“…Although this notion has not been fulfilled and the entire concept of stable differentiation has been challenged, particularly due to the presence of different, highly plastic cell states that might be driven by different molecular alterations [8][9][10], the question remains as to how tumor cells evade these stemness-blocking cues. One factor that has been shown recently to be overexpressed in cancers, including GBM is the secreted BMP4 antagonist CHRDL1 [24,25]. Accordingly, our working hypothesis was that CHRDL1 acts as an enforcer of stemness in GSCs.…”

“…Additionally, it has been proposed that BMP4-treatment of GSCs induces asymmetric divisions favoring stem-like daughter cells [22], while Sachdeva et al propose that BMP signaling mediated by BMP4-treatment induces quiescence [23]. Notably, BMP proteins are antagonized by secreted proteins of the Chordin family [24] including CHRDL1 [25]. In particular, Cyr-Depauw et al showed that CHRDL1 inhibits migration and invasion of breast cancer cells via CHRDL1-mediated BMP4 inhibition [25].…”

BMP Signaling Pathway in Dentin Development and Diseases

“…siRNA GREM2 robustly promoted new bone formation compared to control groups [353]. Chordin (CHD) belongs to a family of proteins that share a cysteine-rich pro-collagen repeat (or chordin-like cysteine-rich repeat (CR)), which is also found in various extracellular matrix proteins [356,357]. Without exception, the homology between CHD family members, including chordin-like 1 (CHDL1) and chordin-like 2 (CHL2), lies within their CRs.…”

“…Without exception, the homology between CHD family members, including chordin-like 1 (CHDL1) and chordin-like 2 (CHL2), lies within their CRs. The CRs within CHD and CHDLs are responsible for BMP binding, specifically and Chordin (CHD) belongs to a family of proteins that share a cysteine-rich pro-collagen repeat (or chordin-like cysteine-rich repeat (CR)), which is also found in various extracellular matrix proteins [356,357]. Without exception, the homology between CHD family members, including chordin-like 1 (CHDL1) and chordin-like 2 (CHL2), lies within their CRs.…”

CHRDL1 Regulates Stemness in Glioma Stem-like Cells

“…Additionally, it has been proposed that BMP4 treatment of GSCs induces asymmetric divisions favoring stem-like daughter cells [ 22 ], while Sachdeva et al proposed that BMP signaling mediated by BMP4-treatment induces quiescence [ 23 ]. Notably, BMP proteins are antagonised by secreted proteins of the Chordin family [ 24 ], including CHRDL1 [ 25 ]. In particular, Cyr-Depauw et al showed that CHRDL1 inhibits the migration and invasion of breast cancer cells via CHRDL1-mediated BMP4 inhibition [ 25 ].…”