The microtubule-associated protein DCAMKL1 regulates osteoblast function via repression of Runx2

J Exp Med. 2013 Aug 26;210(9):1793-806. doi: 10.1084/jem.20111790. Epub 2013 Aug 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bone and Bones / metabolism
  • Cell Differentiation
  • Cells, Cultured
  • Core Binding Factor Alpha 1 Subunit / chemistry
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Core Binding Factor Alpha 1 Subunit / metabolism*
  • Doublecortin-Like Kinases
  • Epistasis, Genetic
  • Gene Silencing
  • Genomics
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lentivirus / metabolism
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Mutant Strains
  • Microtubules / metabolism*
  • Molecular Sequence Data
  • Organ Size
  • Osteoblasts / metabolism*
  • Osteoblasts / pathology
  • Osteoclasts / metabolism
  • Osteoclasts / pathology
  • Phosphorylation
  • Phosphoserine / metabolism
  • Polymerization
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Small Interfering / metabolism

Substances

  • Core Binding Factor Alpha 1 Subunit
  • Intracellular Signaling Peptides and Proteins
  • RNA, Small Interfering
  • RUNX2 protein, human
  • Runx2 protein, mouse
  • Phosphoserine
  • DCLK1 protein, human
  • Doublecortin-Like Kinases
  • Dclk1 protein, mouse
  • Protein Serine-Threonine Kinases