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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2487-2494.
Prepublished online as a Blood First Edition Paper on November 30, 2004; DOI 10.1182/blood-2004-06-2334.
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Submitted June 18, 2004
Accepted November 17, 2004
Frizzled 9 knockout mice have abnormal B cell development
Erik A Ranheim*, Helen C Kwan, Tannishtha Reya, Yu-Ker Wang, Irving L Weissman, and Uta Francke
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
* Corresponding author; email: earanheim{at}wisc.edu.
The binding of frizzled (Fzd) receptors by their Wnt ligands results in the inhibition of  -catenin degradation, and subsequent transcription of -catenin/LEF inducible genes. The -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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