A Novel Chordin-like Protein Inhibitor for Bone Morphogenetic Proteins Expressed Preferentially in Mesenchymal Cell Lineages

Abstract

Chordin is a bone morphogenetic protein (BMP) inhibitor that has been identified as a factor dorsalizing the Xenopus embryo. A novel secreted protein, CHL (for chordin-like), with significant homology to chordin, was isolated from mouse bone marrow stromal cells. Injection of CHL RNA into Xenopus embryos induced a secondary axis. Recombinant CHL protein inhibited the BMP4-dependent differentiation of embryonic stem cells in vitro and interacted directly with BMPs, similar to chordin. However, CHL also weakly bound to TGFbetas. In situ hybridization revealed that the mouse CHL gene, located on the X chromosome, was expressed predominantly in mesenchyme-derived cell types: (1) the dermatome and limb bud mesenchyme and, later, the subdermal mesenchyme and the chondrocytes of the developing skeleton during embryogenesis and (2) a layer of fibroblasts/connective tissue cells in the gastrointestinal tract, the thick straight segments of kidney tubules, and the marrow stromal cells in adults. An exception was expression in the neural cells of the olfactory bulb and cerebellum. Interestingly, the spatiotemporal expression patterns of CHL were distinct from those of chordin in many areas examined. Thus, CHL may serve as an important BMP regulator for differentiating mesenchymal cells, especially during skeletogenesis, and for developing specific neurons.

Chordin-like 1 and Twisted Gastrulation 1 Regulate BMP Signaling following Kidney Injury

“…For example, physical association studies showed that chick CHRDL1 binds to BMP4 but not to BMP7, 46 whereas mouse and human CHRDL1 bind to BMP4 49 and mouse CHRDL1 to BMP5 and BMP6. 47 In a functional osteoblast differentiation assay, rat CHRDL1 binds to and antagonizes BMP7 but not BMP2. 50 In our studies, we demonstrate that human CHRDL1 binds BMP7 in the presence of TWSG1 and ascribe a function to human CHRDL1 similar to that reported for rodent CHRDL1.…”

Secreted bone morphogenetic protein antagonists of the Chordin family

“…Chrdl1 is a Bmp antagonist that binds to BMP4 and BMP6 but not BMP5 and Activin. In contrast to Chordin, Chrdl1 weakly interacts with TGFb1 and TGFb2 (9). Neuralin 1 was identified in the human genome by a homology-based search (23).…”

“…Chrdl1 and Chrdl2 inhibit BMP signaling by binding directly to BMPs (9,10). Although Brorin and Brorin-like also inhibit BMP signaling, it is unclear whether they bind to BMPs (11, 12).…”

“…Later on, Chrdl1 is expressed in discrete regions of the central nervous system and derivatives of the neural crest cells. During organogenesis, Chrdl1 is broadly expressed in many tissues including the dorsal root ganglia, the gut, condensing cartilages of the skeleton, and developing hair follicles (9,23). It is also expressed in the hippocampal astrocytes and dentate granule cells in the brain (25).…”

“…Chordin is a secreted BMP antagonist with highly conserved CR domains (3,7,8). Chordin-like 1 (Chrdl1) and Chordin-like 2 (Chrdl2) were also identified as secreted BMP antagonists with Chordin-like CR domains (9,10). Recently, Brorin and Brorin-like have been identified also (11,12).…”