Conserved regulatory motifs in osteogenic gene promoters integrate cooperative effects of canonical Wnt and BMP pathways

Abstract

Osteoblast differentiation depends on the coordinated network of evolutionary conserved transcription factors during bone formation and homeostasis. Evidence indicates that bone morphogenetic protein (BMP) and Wnt proteins regulate several steps of skeletal development. Here, we provide a molecular description of the cooperative effects of BMP and Wnt canonical pathway on the expression of the early osteogenic genes Dlx5, Msx2, and Runx2 in C2C12 cells, primary cultures of bone marrow-mesenchymal stem cells, and organotypic calvarial cultures. Coordinated regulation of these genes leads to the cooperative activation of their downstream osteogenic target gene osterix. Induction of these genes is mediated through enhancer regions with an evolutionary conserved structure encompassing both Smad and TCF/LEF1 DNA-binding sites. Formation of a cooperative complex is mediated through DNA binding of Smads and TCF4/b-catenin to their cognate sequences, as well as protein-protein interactions between them. The formation of these cooperative transcriptional complexes results in a more efficient recruitment of coactivators such as p300. We propose that evolutionary conserved regulatory regions in specific osteogenic master genes are key integrative modules during osteogenesis. ß

Common Partner Smad-Independent Canonical Bone Morphogenetic Protein Signaling in the Specification Process of the Anterior Rhombic Lip during Cerebellum Development

“…We next investigated whether canonical BMP Smad signaling was activated in the ARL of the Smad4 mutants. The expression of a well-known BMP downstream target, Msx2, was examined (48,49). Msx2 expression similar to that of controls was detected in the ARL of the Smad4 mutant (Fig.…”

Down-regulation of Chondroitin 4-O-Sulfotransferase-1 by Wnt Signaling Triggers Diffusion of Wnt-3a

“…Furthermore, cycloheximide experiments showed that C4ST-1 is an indirect target of BMP2, BMP7, and TGF␤ signaling (31). In addition, it has been reported that bone formation and homeostasis are propelled by integrated cooperative effects of canonical Wnt and BMP pathways (32) and that C4ST-1 is controlled by BMP pathways during chondrogenesis (20). Therefore, it is suggested that C4ST-1 is regulated in a multistep event by Wnt signaling as well as BMP signaling.…”

Molecular Characterization of Cleidocranial Dysplasia (CCD) in the Western Region in KSA

“…Over 90 mutations of RUNX2 have been reported, including chromosomal translocations, deletions, insertions, nonsense and splice-site mutations, and missense mutation (Zheng et al, 2005), Cunningham et al, (2006), Lo Muzio et al, (2007, Lee et al, (2008) and Ryoo et al, (2010). All of these mutations result in loss of function, leading to only 1 functional copy of the gene and subsequent deficient bone formation in a syndrome known as cleidocranial dysplasia (CCD).…”

“…The authors therefore suggested that screening for intragenic deletions and duplications by qPCR or MLPA should be considered for patients with CCD phenotype in whom DNA sequencing does not reveal a causative RUNX2 mutation. Moreover, Ryoo et al, (2010) identified two CCD nuclear families and performed mutational analyses to clarify the underlying molecular genetic etiology. Mutational and phenotypic analyses showed that the severity of mutations on the skeletal system may not necessarily correlate with that of the disruption of tooth development.…”