Editors' ChoiceDevelopmental Biology

Neogenin, a “Neo” Receptor for BMP

Sci. Signal.  22 Feb 2011:
Vol. 4, Issue 161, pp. ec54
DOI: 10.1126/scisignal.4161ec54

Neogenin is a receptor for neuronal guidance cues, such as netrins. Bone morphogenetic proteins (BMPs) control differentiation by signaling through receptors of the transforming growth factor receptor family, such as BMPRs. BMP signaling that triggers bone formation is inhibited by the guanosine triphosphatase Rho and the Rho effector ROCK. Hagihara et al. show that BMPs bind and activate the neogenin receptor, which activates Rho and inhibits BMP-induced osteoblast differentiation by inhibiting activation of the transcriptional regulators Smads, in response to BMP binding to the BMPRs. With a combination of cell-based assays and in vitro assays, the authors demonstrated specific binding of recombinant BMP2, BMP4, BMP6, and BMP7 to neogenin. The interaction between the BMPs and neogenin was detected in cells transfected with neogenin, in C2C12 cells (a pluripotent mesodermal cell line that natively expresses neogenin and BMPRs and can be induced to differentiate into osteoblasts by BMP), and in mouse cerebral cortex lysates. Knockdown of neogenin enhanced BMP-mediated osteoblast differentiation of C2C12 cells, and transcripts for neogenin were increased by BMP, suggesting a feedback loop. Cells in which neogenin was knocked down exhibited enhanced Smad phosphorylation in response to BMP, whereas overexpression of neogenin reduced BMP-induced Smad phosphorylation and the accumulation of Id-1, which is encoded by a Smad target gene. In neogenin knockdown C2C12 cells, BMP failed to stimulate RhoA GTP loading, and expression of a dominant-negative RhoA enhanced BMP-stimulated Smad phosphorylation. Although application of BMP in the presence of a ROCK inhibitor failed to enhance Smad phosphorylation, the C2C12 cells had increased production of alkaline phosphatase (ALP, a marker of bone cells) relative to cells only exposed to BMP. Thus, BMP appears to stimulate two signaling systems—a positive one through the BMPRs and a negative one through neogenin, which appears to inhibit BMPR signaling through at least two mechanisms.

M. Hagihara, M. Endo, K. Hata, C. Higuchi, K. Takaoka, H. Yoshikawa, T. Yamashita, Neogenin, a receptor for bone morphogenetic proteins. J. Biol. Chem. 286, 5157–5165 (2011). [Abstract] [Full Text]