A novel chordin-like protein inhibitor for bone morphogenetic proteins expressed preferentially in mesenchymal cell lineages

Chordin is a bone morphogenetic protein (BMP) inhibitor that has been ident ified 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 em bryos induced a secondary axis. Recombinant CHL protein inhibited the BMP4- dependent differentiation of embryonic stem cells in vitro and interacted d irectly with BMPs, similar to chordin. However, CHL also weakly bound to TG F betas. In situ hybridization revealed that the mouse CHL gene, located on the X chromosome, was expressed predominantly in mesenchyme-derived cell t ypes: (1) the dermatome and limb bud mesenchyme and, later, the subdermal m esenchyme and the chondrocytes of the developing skeleton during embryogene sis and (2) a layer of fibroblasts/connective tissue cells in the gastroint estinal tract, the thick straight segments of kidney tubules, and the marro w stromal cells in adults. An exception was expression in the neural cells of the olfactory bulb and cerebellum. Interestingly, the spatiotemporal exp ression patterns of CHL were distinct from those of chordin in many areas e xamined. Thus, CHL may serve as an important BMP regulator for differentiat ing mesenchymal cells, especially during skeletogenesis, and for developing specific neurons. (C) 2001 Academic Press.