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: 3.64). 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.

0 Followers
 · 
111 Views
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mesenchymal stromal cells (MSCs) are of high relevance for the regeneration of mesenchymal tissues such as bone and cartilage. The promising role of MSCs in cell-based therapies and tissue engineering appears to be limited due to a decline of their regenerative potential with increasing donor age, their limited availability in human tissues and the need of in vitro expansion prior to treatment. We therefore aimed to determine to which degree in vitro aging and chronological aging may be similar processes or if in vitro culture-related changes at the cellular and molecular level are at least altered as a function of donor age. For that purpose we established MSCs cultures from young (yMSCs) and aged (aMSCs) rats that were cultured for more than 100 passages. These long-term MSCs cultures were non-tumorigenic and exhibited similar surface marker patterns as primary MSCs of passage 2. During in vitro expansion, but not during chronological aging, MSCs progressively lose their progenitor characteristics, e.g., complete loss of osteogenic differentiation potential, diminished adipogenic differentiation, altered cell morphology and increased susceptibility towards senescence. Transcriptome analysis revealed that long-term in vitro MSCs cultivation leads to down-regulation of genes involved in cell differentiation, focal adhesion organization, cytoskeleton turnover and mitochondria function. Accordingly, functional analysis demonstrated altered mitochondrial morphology, decreased antioxidant capacities and elevated ROS levels in long-term cultivated yMSCs as well as aMSCs. Notably, only the MSC migration potential and their antioxidative capacity were altered by in vitro as well as chronological aging. Based on specific differences observed between the impact of chronological and in vitro MSC aging we conclude that both are distinct processes.
    PLoS ONE 12/2012; 7(12):e52700. DOI:10.1371/journal.pone.0052700 · 3.23 Impact Factor
Show more

Preview

Download
3 Downloads
Available from