title: The microtubule-associated protein DCAMKL1 regulates osteoblast function via repression of Runx2.
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.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. zouwg94@sibcb.ac.cn
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zou
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Greenblatt
authors.forename: Nicholas
authors.initials: N
authors.lastname: Brady
authors.forename: Sutada
authors.initials: S
authors.lastname: Lotinun
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.forename: Heather
authors.initials: H
authors.lastname: de Rivera
authors.forename: Anju
authors.initials: A
authors.lastname: Singh
authors.forename: Jun
authors.initials: J
authors.lastname: Sun
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Dallas C
authors.initials: DC
authors.lastname: Jones
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000089742:Doublecortin-Like Kinases; D004843:Epistasis, Genetic; D020868:Gene Silencing; D023281:Genomics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016086:Lentivirus / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008870:Microtubules / Q000378:metabolism*; D008969:Molecular Sequence Data; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D058105:Polymerization; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C493709:RUNX2 protein, human; C493716:Runx2 protein, mouse; D010768:Phosphoserine; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases
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