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Frizzled 9 knock-out mice have abnormal B-cell development
Erik A Ranheim1, Helen C K Kwan, Tannishtha Reya
1Departments of Pathology and Genetics, Stanford University School of Medicine, Stanford, CA, USA. earanheim@wisc.edu
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.
Insights
Frizzled-9 (Fzd9) signaling is crucial for B cell development in mice, impacting pre-B cell expansion and lymphoid organ maturation. Loss of Fzd9 leads to defects in B cell development and lymphoid abnormalities.
Area of Science:
- Immunology
- Developmental Biology
- Genetics
Background:
- The Wnt/beta-catenin pathway regulates gene transcription involved in development and disease.
- FZD9, a gene on chromosome 7q11.23, is implicated in the neurodevelopmental disorder Williams-Beuren syndrome.
- Fzd9's role in the immune system, particularly in lymphoid development, is not well understood.
Purpose of the Study:
- To investigate the function of Frizzled-9 (Fzd9) in lymphoid development and maturation.
- To characterize the B cell development defects in Fzd9 knockout mice.
- To determine if Fzd9 plays a role in B cell self-renewal and differentiation.
Main Methods:
- Analysis of Fzd9 knockout (Fzd9-/-) mice for lymphoid phenotypes.
- Flow cytometry to assess B cell populations in bone marrow, thymus, and spleen.
- Competitive bone marrow reconstitution assays to evaluate hematopoietic stem cell function.
Main Results:
- Fzd9-/- mice exhibit splenomegaly, thymic atrophy, and lymphadenopathy with age.
- A significant depletion of developing B cells, particularly at the pre-B stage, was observed in the bone marrow of Fzd9-/- mice.
- Bone marrow from Fzd9-/- mice showed intrinsic defects in B cell development in competitive transplantation studies.
- Mature B cell numbers were normal in the lymph nodes and spleen of Fzd9-/- mice.
Conclusions:
- Fzd9 signaling is essential for normal B cell development, specifically during the pre-B cell stage of clonal expansion.
- Fzd9 plays a critical role in the self-renewal and differentiation of B cells within the lymphoid system.
- These findings highlight Fzd9 as a key regulator of adaptive immunity and B cell homeostasis.
