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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    • "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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    • "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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