Notch Signaling Bone Notches

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Notch proteins are transmembrane receptors that are activated by their ligands, members of the Jagged and Delta-like families, which are present on the surfaces of adjacent cells. After ligand-binding, Notch proteins are processed by the -secretase complex, which releases the Notch intracellular domain (ICD), allowing it to translocate to the nucleus and activate gene transcription. Notch signaling is important in the control of cell fate during development, but Hilton et al. investigated a role for Notch in the regulation of mesenchymal progenitor cells, the precursors of osteoblasts, in the bone marrow. Mice in which deletion of Notch1 and Notch2 was restricted to the limb mesenchyme (PNN mice) had, when 8 weeks of age, shorter long bones and increased bone radiodensity, as analyzed by x-ray radiography, than did wild-type mice. This skeletal phenotype was also observed in mice in which the -secretase complex catalytic subunits presenilin-1 and presenilin-2 were absent from the limb mesenchyme (PPS mice). The increased radiodensity in PNN and PPS mice was due to the presence of bone within the marrow cavity, which correlated with an increase in the number of active osteoblasts compared with that in wild-type mice. Similar defects were found in the embryos of PNN and PPS mice. Further experiments showed that, whereas mesenchymal progenitor cells were present in the bone marrow of wild-type mice, they were undetectable in PNN mice. This lack of progenitor cells correlated with a progressive loss of bone density in the PNN mice as they aged. These data suggest that Notch signaling helps to maintain a pool of progenitor cells in the bone marrow by inhibiting their differentiation into osteoblasts.

M. J. Hilton, X. Tu, X. Wu, S. Bai, H. Zhao, T. Kobayashi, H. M. Kronenberg, S. L. Teitelbaum, F. P. Ross, R. Kopan, F. Long, Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat. Med. 14, 306-314 (2008). [PubMed]