Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Atrophy / immunology
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Atrophy / metabolism
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Atrophy / pathology
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology
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Bone Marrow Cells / immunology
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / pathology
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Bone Marrow Transplantation
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Chromosomes, Human, Pair 7 / genetics
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Chromosomes, Human, Pair 7 / immunology
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Frizzled Receptors
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Humans
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Immunoglobulin Light Chains / genetics
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Immunoglobulin Light Chains / immunology
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Lymph Nodes / pathology
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Lymphatic Diseases / immunology
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Lymphatic Diseases / metabolism
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Lymphatic Diseases / pathology
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Lymphopoiesis / genetics
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Lymphopoiesis / immunology*
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Mice
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Mice, Knockout
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Receptors, Neurotransmitter / genetics
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Receptors, Neurotransmitter / immunology*
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Somatic Hypermutation, Immunoglobulin / genetics
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Somatic Hypermutation, Immunoglobulin / immunology
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Spleen / immunology
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Spleen / metabolism
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Spleen / pathology
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TCF Transcription Factors / immunology
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TCF Transcription Factors / metabolism
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Thymus Gland / immunology
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Thymus Gland / metabolism
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Thymus Gland / pathology
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Williams Syndrome / genetics
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Williams Syndrome / immunology
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Williams Syndrome / metabolism
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Williams Syndrome / pathology
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beta Catenin / biosynthesis
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beta Catenin / immunology
Substances
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Frizzled Receptors
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Fzd9 protein, mouse
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Immunoglobulin Light Chains
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Receptors, Neurotransmitter
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TCF Transcription Factors
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beta Catenin