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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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IMMUNOBIOLOGY
Frizzled 9 knock-out mice have abnormal B-cell development
Erik A. Ranheim,
Helen C. K. Kwan,
Tannishtha Reya,
Yu-Ker Wang,
Irving L. Weissman, and
Uta Francke
From the Departments of Pathology and Genetics, Stanford University School of Medicine, Stanford, CA.
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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