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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


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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    • "Finally, we compared the healing response of Sost À/À mice to another animal model with enhanced b-catenin signaling. Axin2 À/À mice demonstrate high osteoblastic bone formation activity in both axial and appendicular skeletal sites due to enhanced canonical Wnt/b-catenin signaling that increases progenitor cell proliferation [22] [24] [30]. We previously reported that bone marrow-derived osteoblast progenitors from Axin2 À/À animals rapidly Fig. 4. Bone defect healing is accelerated in Axin2 À/À mice. "
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    ABSTRACT: We investigated the influence of the osteocyte protein, sclerostin, on fracture healing by examining the dynamics and mechanisms of repair of single-cortex, stabilized femoral defects in sclerostin knockout (Sost(-/-); KO) and sclerostin wild-type (Sost(+/+); WT) mice. Fourteen days following generation of bone defects, Sost KO mice had significantly more bone in the healing defect than WT mice. The increase in regenerating bone was due to an increase in the thickness of trabecularized spicules, osteoblast numbers and surfaces within the defect. Enhanced healing of bone defects in Sost KO mice was associated with significantly more activated β-catenin expression than observed in WT mice. The findings were similar to those observed in Axin2(-/-) mice, in which β-catenin signaling is known to be enhanced to facilitate bone regeneration. Taken together, these data indicate that enhanced β-catenin signaling is present in Sost(-/-) mice that demonstrate accelerated healing of bone defects, suggesting that modulation of β-catenin signaling in bone could be used to promote fracture repair.
    Biochemical and Biophysical Research Communications 11/2013; 441(4). DOI:10.1016/j.bbrc.2013.10.155 · 2.30 Impact Factor
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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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    ABSTRACT: Wnt signaling is required for both the development and homeostasis of the skin, yet its contribution to skin wound repair remains controversial. By employing Axin2(LacZ/+) reporter mice we evaluated the spatial and temporal distribution patterns of Wnt responsive cells, and found that the pattern of Wnt responsiveness varies with the hair cycle, and correlates with wound healing potential. Using Axin2(LacZ/LacZ) mice and an ear wound model, we demonstrate that amplified Wnt signaling leads to improved healing. Utilizing a biochemical approach that mimics the amplified Wnt response of Axin2(LacZ/LacZ) mice, we show that topical application of liposomal Wnt3a to a non-healing wound enhances endogenous Wnt signaling, and results in better skin wound healing. Given the importance of Wnt signaling in the maintenance and repair of skin, liposomal Wnt3a may have widespread application in clinical practice.
    PLoS ONE 10/2013; 8(10):e76883. DOI:10.1371/journal.pone.0076883 · 3.23 Impact Factor
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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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    ABSTRACT: Aberrant regulation of the Wnt pathway, essential for various developmental processes, is tightly linked to human breast cancers. By hijacking this evolutionary conserved signaling pathway, cancer cells acquire sustaining proliferation ability, leading to modification of physiologic properties necessary for tumor initiation and progression. An enormous wealth of knowledge on the importance of Wnt signaling in breast development and cancer has been obtained, but the cell types responsible for production of this proliferative signal operating within normal and malignant tissues remains poorly understood. Here we report that Wnt production mediated by Gpr177 is essential for mammary morphogenesis. The loss of Gpr177 interferes with mammary stem cells, leading to deficiencies in cell proliferation and differentiation. Genetic analysis further demonstrates an indispensable role of Gpr177 in Wnt-induced tumorigenesis. The Gpr177-deficiency mice are resistant to malignant transformation. This study not only demonstrates the necessity of Wnt in mammary organogenesis but also provides a proof-of-principle for targeting of Gpr177 as a potential new treatment for human diseases with aberrant Wnt stimulation.
    PLoS ONE 02/2013; 8(2):e56644. DOI:10.1371/journal.pone.0056644 · 3.23 Impact Factor
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