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: 3.64). 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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    • "There is one caveat to the experiments conducted in Axin2LacZ/LacZ mice. These mice appear to have more stem cells in their adult tissues, and these tissue-resident stem cells may enhance cell proliferation during healing [29], [40]. Also, in Axin2LacZ/LacZ mice Wnt signaling is amplified in all tissue compartments. "
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    • "For histological evaluation, tissues were dissected, fixed in 10% buffered formalin and paraffin embedded to obtain sections which were stained with hematoxylin/eosin. Sections were subject to immunostaining with avidin∶biotinlylated enzyme complex as described [27], [31], [35], [36], [37]. The immunological staining was visualized by enzymatic color reaction, fluorescence or electron microscopy. "
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    • "Results from several studies have led to the assumption that the BMP pathway cooperates with other pathways, especially the canonical Wnt-signaling [46]–[48], to drive osteogenic differentiation. For example, the knock-out of the Wnt/ß-catenin antagonist Axin2 leads to enhanced nuclear accumulation of ß-catenin and increased levels of BMP2, BMP6 and phosphor-Smad, which further promotes osteogenic differentiation of osteoprogenitor cells and enhances bone formation in vitro and in vivo, respectively [49], [50]. In both studies, the effect of the Axin2 knockout on BMP-signaling and osteogenic differentiation could be reversed by ß-catenin inactivation. "
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