Progression of calvarial bone development requires Foxc1 regulation of Msx2 and Alx4

Rice, Ritva; Rice, David; Olsen, Bjørn R.; Thesleff, Irma

doi:10.1016/s0012-1606(03)00355-5

Cited by 119 publications

(164 citation statements)

References 42 publications

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“…The mechanism by which Foxc1 regulates skeletal development has previously been investigated from the viewpoint of intramembranous bone formation with particular focus on osteoblasts, not endochondral ossification. Thus, several groups have reported the importance of bone morphogenetic protein signalling and Msx2 in Foxc1-dependent calvarial bone development [46][47][48] . Although Alcian blue-positive nodule formation of mesenchymal cells isolated from Foxc1 lacZ embryos has been studied 45 , the molecular mechanisms by which Foxc1 controls endochondral formation are largely unknown.…”

Section: Discussionmentioning

confidence: 99%

The transcription factor Foxc1 is necessary for Ihh–Gli2-regulated endochondral ossification

et al. 2015

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Section: Discussionmentioning

confidence: 99%

The transcription factor Foxc1 is necessary for Ihh–Gli2-regulated endochondral ossification

et al. 2015

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“…Previous reports have indicated that Msx2 plays a critical role in the proliferation of osteoprogenitor cells in the osteogenic fronts of the suture area (22,33). The cranial suture is a mass of soft tissue between two calvarial bones and is the growing front of the calvarial flat bones.…”

Section: Discussionmentioning

confidence: 99%

The Boston-type Craniosynostosis Mutation MSX2 (P148H) Results in Enhanced Susceptibility of MSX2 to Ubiquitin-dependent Degradation

Yoon

Cho

et al. 2008

Journal of Biological Chemistry

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Boston-type craniosynostosis is caused by a single amino acid substitution, P148H, in the transcription factor MSX2. The increased binding affinity of MSX2 (P148H) to the response element has led many to hypothesize that the substitution is a gainof-function mutation. However, there have been conflicting reports on the function of MSX2, and by extension, the nature of the P148H mutation remains unclear. In this study, we have examined the molecular mechanism of MSX2 function and the nature of the P148H mutation. During cranial suture closure of rodent, Msx2 expression was detected in the suture space. Overexpression of wild type MSX2 in mesenchymal cells stimulated cell proliferation and cyclin D1 expression, whereas P148H mutant did not. These results indicated that MSX2 is involved in maintaining the suture space by stimulating suture mesenchymal cell proliferation and that P148H is defective in this process. The protein levels of P148H were lower than wild type Msx2 (Msx2-WT), and pulse-chase experiments indicated that the mutant protein has a shorter half-life than the Msx2-WT protein. The ubiquitylation level of P148H was greater than that of Msx2-WT. The degradation of Msx2 was mediated by Praja1, and the P148H mutant was degraded more effectively than WT. The ubiquitylation of Msx2-WT was higher in the presence of Msx2 (P148H), which indicated that P148H functions as a dominant-negative mutant. Collectively, the primary function of MSX2 in suture closure is the induction of cell proliferation and suture maintenance, and the mutation results in an increased susceptibility of both wild type and mutant MSX2 to proteasomal degradation.

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“…BMP2 and BMP4 stimulate cranial suture closure by activating their downstream targets Dlx5 (Holleville et al, 2003) and Msx2 (Rice et al, 2003). Our recent report indicates that the expression of the osteogenic master transcription factor, Runx2, is stimulated by BMP signaling and that Dlx5 mediates this signaling process (Lee et al, 2003a).…”

Section: Introductionmentioning

confidence: 98%

Runx2 regulates FGF2-inducedBmp2 expression during cranial bone development

et al. 2005

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Calvarial bone is formed by the intramembranous bone-forming process, which involves many signaling molecules. The constitutive activation of the fibroblast growth factor (FGF) signaling pathway accelerates osteoblast differentiation and results in premature cranial suture closure. Bone morphogenetic protein (BMP) signaling pathways, which involve the downstream transcription factors Dlx5 and Msx2, are also involved in the bone-forming processes. However, the relationships between these two main signaling cascades are still unclear. We found that FGF2 treatment of developing bone fronts stimulated Bmp2 gene expression but that BMP2 treatment could not induce Fgf2 expression. Moreover, the disruption of the Runx2 gene completely eliminated the expression of Bmp2 and its downstream genes Dlx5 and Msx2 in the developing primordium of bone, while the expression of Fgf2 was maintained. In addition, cultured Runx2؊/؊ cells expressed very low baseline levels of Bmp2 that were up-regulated by transfection with a Runx2-expressing plasmid. These levels in turn were markedly elevated by FGF2 treatment. FGF2 treatment also strongly enhanced the Bmp2 expression in MC3T3-E1 cells, whose endogenous Runx2 gene is intact and which express Bmp2 at low baseline levels as well. These results indicate that Runx2 is an important mediator of the expression of Bmp2 in response to FGF stimulation in cranial bone development.

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Progression of calvarial bone development requires Foxc1 regulation of Msx2 and Alx4

Cited by 119 publications

References 42 publications

The transcription factor Foxc1 is necessary for Ihh–Gli2-regulated endochondral ossification

The transcription factor Foxc1 is necessary for Ihh–Gli2-regulated endochondral ossification

The Boston-type Craniosynostosis Mutation MSX2 (P148H) Results in Enhanced Susceptibility of MSX2 to Ubiquitin-dependent Degradation

Runx2 regulates FGF2-inducedBmp2 expression during cranial bone development

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