Title | The microtubule-associated protein DCAMKL1 regulates osteoblast function via repression of Runx2. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Zou W, Greenblatt MB, Brady N, Lotinun S, Zhai B, de Rivera H, Singh A, Sun J, Gygi SP, Baron R, Glimcher LH, Jones DC |
Journal | J Exp Med |
Volume | 210 |
Issue | 9 |
Pagination | 1793-806 |
Date Published | 2013 Aug 26 |
ISSN | 1540-9538 |
Keywords | Amino Acid Sequence, Animals, Bone and Bones, Cell Differentiation, Cells, Cultured, Core Binding Factor Alpha 1 Subunit, Epistasis, Genetic, Gene Silencing, Genomics, Humans, Intracellular Signaling Peptides and Proteins, Lentivirus, Mesenchymal Stem Cells, Mice, Mice, Mutant Strains, Microtubules, Molecular Sequence Data, Organ Size, Osteoblasts, Osteoclasts, Phosphorylation, Phosphoserine, Polymerization, Protein-Serine-Threonine Kinases, RNA, Small Interfering |
Abstract | Osteoblasts are responsible for the formation and mineralization of the skeleton. To identify novel regulators of osteoblast differentiation, we conducted an unbiased forward genetic screen using a lentiviral-based shRNA library. This functional genomics analysis led to the identification of the microtubule-associated protein DCAMKL1 (Doublecortin-like and CAM kinase-like 1) as a novel regulator of osteogenesis. Mice with a targeted disruption of Dcamkl1 displayed elevated bone mass secondary to increased bone formation by osteoblasts. Molecular experiments demonstrated that DCAMKL1 represses osteoblast activation by antagonizing Runx2, the master transcription factor in osteoblasts. Key elements of the cleidocranial dysplasia phenotype observed in Runx2(+/-) mice are reversed by the introduction of a Dcamkl1-null allele. Our results establish a genetic linkage between these two proteins in vivo and demonstrate that DCAMKL1 is a physiologically relevant regulator of anabolic bone formation. |
DOI | 10.1084/jem.20111790 |
Alternate Journal | J Exp Med |
PubMed ID | 23918955 |
Grant List | HD055601 / HD / NICHD NIH HHS / United States K99AR055668 / AR / NIAMS NIH HHS / United States |
Related Faculty:
Matthew B. Greenblatt, M.D., Ph.D.