Frizzled 9 knock-out mice have abnormal B-cell development.
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.
Ranheim
Erik A
EA
Departments of Pathology and Genetics, Stanford University School of Medicine, Stanford, CA, USA. earanheim@wisc.edu
Kwan
Helen C K
HC
Reya
Tannishtha
T
Wang
Yu-Ker
YK
Weissman
Irving L
IL
Francke
Uta
U
D000818:Animals; D001284:Atrophy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics / Q000276:immunology; D051157:Frizzled Receptors; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008206:Lymphatic Diseases / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D017981:Receptors, Neurotransmitter / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051820:TCF Transcription Factors / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018980:Williams Syndrome / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051176:beta Catenin / Q000096:biosynthesis / Q000276:immunology
D051157:Frizzled Receptors; C403212:Fzd9 protein, mouse; D007147:Immunoglobulin Light Chains; D017981:Receptors, Neurotransmitter; D051820:TCF Transcription Factors; D051176:beta Catenin