Article

Craniosynostosis caused by Axin2 deficiency is mediated through distinct functions of β-catenin in proliferation and differentiation

Department of Biomedical Genetics, Center for Oral Biology, Abs Institute of Biomedical Sciences, University of Rochester Medical Center, Rochester, NY 14642, USA.
Developmental Biology (Impact Factor: 3.55). 02/2007; 301(1):298-308. DOI: 10.1016/j.ydbio.2006.10.018
Source: PubMed

ABSTRACT

Targeted disruption of Axin2 in mice induces skeletal defects, a phenotype resembling craniosynostosis in humans. Premature fusion of cranial sutures, caused by deficiency in intramembranous ossification, occurs at early postnatal stages. Axin2 negatively regulates both expansion of osteoprogenitors and maturation of osteoblasts through its modulation on Wnt/beta-catenin signaling. We investigate the dual role of beta-catenin to gain further insights into the skull morphogenetic circuitry. We show that as a transcriptional co-activator, beta-catenin promotes cell division by stimulating its target cyclin D1 in osteoprogenitors. Upon differentiation of osteoprogenitors, BMP signaling is elevated to accelerate the process in a positive feedback mechanism. This Wnt-dependent BMP signal dictates cellular distribution of beta-catenin. As an adhesion molecule, beta-catenin promotes cell-cell interaction mediated by adherens junctions in mature osteoblasts. Finally, haploid deficiency of beta-catenin alleviates the Axin2-null skeletal phenotypes. These findings support a model for disparate roles of beta-catenin in osteoblast proliferation and differentiation.

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    • "In vitro addition of FGF to osteoblasts downregulates several Wnt target genes suppressing osteoblast differentiation, and concomitantly upregulates the transcription factor SOX2 which carries the inherent ability to suppress Wnt signaling pathways [79]. The osteoblast inhibiting properties of Wnt signals may occur independently, or alongside with bone morphogenetic proteins (BMPs) [80]. Interestingly, exposure of osteogenic fronts and mid-sutural mesenchyme to BMP4 did not generate synostosis, but did render increased tissue volume within both areas. "
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    • "In vitro addition of FGF to osteoblasts downregulates several Wnt target genes suppressing osteoblast differentiation, and concomitantly upregulates the transcription factor SOX2 which carries the inherent ability to suppress Wnt signaling pathways [79]. The osteoblast inhibiting properties of Wnt signals may occur independently, or alongside with bone morphogenetic proteins (BMPs) [80]. Interestingly, exposure of osteogenic fronts and mid-sutural mesenchyme to BMP4 did not generate synostosis, but did render increased tissue volume within both areas. "
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