Loss of Fancc Impairs Antibody-Secreting Cell Differentiation in Mice through Deregulating the Wnt Signaling Pathway

Abstract

Fanconi anemia (FA) is characterized by a progressive bone marrow failure and an increased incidence of cancer. FA patients have high susceptibility to immune-related complications such as infection and post-transplant graft-versus-host-disease. Here we investigated the effect of FA deficiency in B cell function using the Fancc mouse model. Fancc−/− B cells show a specific defect in IgG2a switch and impaired Antibody-Secreting-Cell (ASC) differentiation. Global transcriptome analysis of naïve B cells by RNAseq demonstrates that FA deficiency deregulates a network of genes involved in immune function. Significantly, many genes implicated in Wnt signaling were aberrantly expressed in Fancc−/− B cells. Consistently, Fancc−/− B cells accumulate high levels of β-catenin under both resting and stimulated conditions, suggesting hyper-active Wnt signaling. Using an in-vivo Wnt GFP reporter assay, we verified the up-regulation of Wnt signaling as a potential mechanism responsible for the impaired Fancc−/− B cell differentiation. Further, we showed that Wnt signaling inhibits ASC differentiation possibly through repression of Blimp1 and that Fancc−/− B cells are hypersensitive to Wnt activation during ASC differentiation. Our findings identify Wnt signaling as a physiological regulator of ASC differentiation and establish a role for the Wnt pathway in normal B cell function and FA immune deficiency.

BATF regulates the expression of Nfil3, Wnt10a and miR155hg for efficient induction of antibody class switch recombination in mice

“…The positioning of BATF as an early, or pioneering, regulator of a diverse gene set impacting transcription events (Nfil3), post-transcriptional events (miR155gh), and cellular signaling (Wnt10a) is very exciting. While the negative impact of canonical WNT signaling on CSR was noted previously [36], a role for WNT10A expression was not, and the availability of recombinant WNT10A and WNT pathway inhibitors should facilitate future investigations of this pathway in CSR. Finally, as BATF, NFIL3 and miR155 are known regulators Th2, Th17 and Tfh cell differentiation and function [10,11,13,42,43], it is not surprising that the BATF targets studied here are also misregulated in Batf Z/ Z CD4+ T cells (Morman and Taparowsky, in preparation).…”

Deletion of the Fanconi Anemia C Gene in Mice Leads to Skeletal Anomalies and Defective Bone Mineralization and Microarchitecture

“…In addition, serum DKK1 levels were found to correlate with BMD parameters in patients with osteoporosis . Interestingly, we and others have reported dysregulated Wnt signaling in cells derived from FA‐mutant mice and from patients with FA . Moreover, we previously reported DKK1 overproduction in FA‐deficient cells and in sera from FA mouse models …”

“…(55) FA patient-derived cells were shown to have a dysregulated Wnt/b-catenin signal shown by lack of b-catenin activation and altered expression of Wnt/b-catenin target genes. (28)(29)(30) One of the Wnt/b-catenin dysregulated genes found in FA is DKK1. DKK1 has been shown to favor adipogenesis over osteogenesis.…”

“…For instance, binding of PPARγ to β‐catenin lead to rapid degradation of β‐catenin, which activate preadipocyte differentiation . FA patient‐derived cells were shown to have a dysregulated Wnt/β‐catenin signal shown by lack of β‐catenin activation and altered expression of Wnt/β‐catenin target genes . One of the Wnt/β‐catenin dysregulated genes found in FA is DKK1 .…”

Sclerostin Deficiency Alters Peripheral B Lymphocyte Responses in Mice

“…This suggests that there is a role of Sost on innate-like B cells or their microenvironments (30) responses to antigen were observed in vivo (31) . Mice that lack the Fanconi anemia gene Fancc experience progressive bone marrow failure, and Fancc -/-B cells display enhanced Wnt signaling, impaired B cell survival and impaired generation of antibody-secreting cells (32) . The role of noncanonical Wnt signaling in B cell development has also produced conflicting results.…”