Ranheim, E. A. et al. Frizzled 9 knock-out mice have abnormal B-cell development. Blood 105, 2487-2494

Stanford University, Palo Alto, California, United States
Blood (Impact Factor: 10.45). 04/2005; 105(6):2487-94. DOI: 10.1182/blood-2004-06-2334
Source: PubMed


The binding of frizzled (Fzd) receptors by their Wnt ligands results in the inhibition of beta-catenin degradation and subsequent transcription of beta-catenin/LEF-inducible genes. The beta-catenin pathway is known to be involved in development, tumorigenesis, and stem cell self-renewal. In humans, the FZD9 gene lies in the region of chromosome 7q11.23 deleted in the neurodevelopmental disorder, Williams-Beuren syndrome (WBS). Fzd9-/- mice show no obvious features of WBS, but reveal a role for Fzd9 in lymphoid development and maturation. Fzd9-/- mice show pronounced splenomegaly, thymic atrophy, and lymphadenopathy with age, with accumulation of plasma cells in lymph nodes. There is a depletion of developing B cells in the bone marrow (BM), particularly in the pre-B stage where immunoglobulin heavy chains are expressed and the cells are undergoing clonal expansion prior to light chain rearrangement. The pre-B defect is partially intrinsic to the hematopoietic system; as in competitive BM reconstitution studies, Fzd9-/- -derived BM exhibits defective B-cell development when implanted into a wild-type host. Mature B cells are present in normal numbers in lymph node and spleen. These findings suggest a role for Fzd9 signaling in lymphoid development, particularly at points where B cells undergo self-renewal prior to further differentiation.

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Available from: Erik Ranheim, Jul 21, 2014
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    • "GPCRs are diverse in structure and function but can be phylogenetically categorized into 5 primary receptor families: rhodopsin, glutamate , frizzled/taste2, adhesion, and secretin (Fredriksson et al., 2003). GPCRs of particular relevance to hematopoietic development can be found in the rhodopsin family (chemokine C-X-C motif receptor 4 (CXCR4) and sphingosine 1-phosphate receptor (S1PR1/EDG1)), glutamate family (calcium sensing receptor (CaSR)), and frizzled family (Wnt receptors Smoothened (SMOH), Frizzled 4 (FZD4), and FZD9) (Adams et al., 2006; Corrigan et al., 2009; Gering and Patient, 2005; Ranheim et al., 2005; Seitz et al., 2005; Zou et al., 1998). Functions of these receptors in hematopoiesis include regulation of lineage specification and homing. "
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    ABSTRACT: The hematopoietic system is dynamic during development and in adulthood, undergoing countless spatial and temporal transitions during the course of one's life. Microenvironmental cues in the many unique hematopoietic niches differ, characterized by distinct soluble molecules, membrane-bound factors, and biophysical features that meet the changing needs of the blood system. Research from the last decade has revealed the importance of substrate elasticity and biomechanical force in determination of stem cell fate. Our understanding of the role of these factors in hematopoiesis is still relatively poor; however, the developmental origin of blood cells from the endothelium provides a model for comparison. Many endothelial mechanical sensors and second messenger systems may also determine hematopoietic stem cell fate, self renewal, and homing behaviors. Further, the intimate contact of hematopoietic cells with mechanosensitive cell types, including osteoblasts, endothelial cells, mesenchymal stem cells, and pericytes, places them in close proximity to paracrine signaling downstream of mechanical signals. The objective of this review is to present an overview of the sensors and intracellular signaling pathways activated by mechanical cues and highlight the role of mechanotransductive pathways in hematopoiesis.
    Differentiation 07/2013; 86(3). DOI:10.1016/j.diff.2013.06.004 · 3.44 Impact Factor
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    • "More recently, gain of function studies have demonstrated that constitutively activated β-catenin in hematopoietic stem cells blocks multilineage differentiation; including B cell differentiation at early stages, suggesting the importance of fine tuning of Wnt/β-catenin signaling pathway for normal B cell development and function [43,44]. Frizzled 9 knockout in mice leads to abnormal B-cell development [45]. Wnt signaling is required for thymocyte development[46] and plays a key role in the maintenance of stemness in mature memory CD8+T cells[47]. "
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    ABSTRACT: Wnt canonical signaling pathway plays a diverse role in embryonic development and maintenance of organs and tissues in adults. It has been observed that Wnt/β-catenin signaling pathway is involved in the pathogenesis of many carcinomas. Moreover, Wnt/β-catenin pathway has been revealed to be associated with angiogenesis. Wnt canonical pathway signaling has great potential as a therapeutic target. It has been disclosed that some hematological malignancies, such as chronic lymphocytic leukemia, mantle cell lymphoma, may occur partly due to the constitutive activation of Wnt canonical signaling pathway. This review will summarize the latest development in Wnt canonical signaling pathway and its roles in tumorigenesis and angiogenesis.
    Journal of Hematology & Oncology 09/2010; 3(33):33. DOI:10.1186/1756-8722-3-33 · 4.81 Impact Factor
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    • "In the adult mouse, FZD9 mRNA expression is abundant in the heart, brain, skeletal muscle, kidney, and testis (Wang et al., 1999). FZD9 gene deletion leads to abnormal B-cell development and hippocampal and visuospatial learning defects that may ultimately lead to Williams syndrome (Ranheim et al., 2005; Zhao et al., 2005). In humans, overexpression of FZD9 mRNA was detected in some cases of gastric cancer and astrocytomas (Zhang et al., 2006). "
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    ABSTRACT: We have recently shown that frizzled-9 (FZD9, CD349) is expressed on the cell surface of cultured mesenchymal stromal cells (MSC) derived from the human bone marrow (BM) and chorionic placenta (PL). To study whether FZD9 is also a marker for naive mesenchymal stem cells (MSC), we analyzed the expression pattern of FZD9 on freshly isolated PL cells and determined the clonogenic potential of isolated FZD9(+) cells using the colony-forming units-fibroblastic (CFU-F) assay. About 0.2% of isolated PL cells were positive for FZD9. Two-color analysis revealed that FZD9(+) PL cells uniformly express CD9, CD63, and CD90, but are heterogeneous for CD10, CD13, and CD26 expression. In contrast to BM-derived MSC, PL-derived MSC expressed only low levels of CD271. Colony assays of sorted cells showed that clonogenic CFU-F reside exclusively in the FZD9(+) but not in the FZD9(-) fraction. Further analysis revealed that CFU-F were enriched by 60-fold in the FZD9(+)CD10(+)CD26(+) fraction but were absent in the FZD9(+)CD10(-)CD26(-) population. Cultured FZD9(+) cells expressed the embryonic stem cell makers Oct-4 and nanog as well as SSEA-4 and TRA1-2-49/6E. In addition, they could be differentiated into functional adipocytes and osteoblasts. This report describes for the first time that FZD9 is a novel and specific marker for the prospective isolation of MSC from human term PL.
    Differentiation 05/2008; 76(4):326-36. DOI:10.1111/j.1432-0436.2007.00225.x · 3.44 Impact Factor
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