Regulation of Marginal Zone B Cell Development by MINT, a Suppressor of Notch/RBP-J Signaling Pathway

Kuroda, Kazuki; Han, Hua; Tani, Shoichi; Tanigaki, Kenji; Tun, Tin; Furukawa, Takahisa; Taniguchi, Yoshihito; Kurooka, Hisanori; Hamada, Y.; Toyokuni, Shinya; Honjo, Tasuku

doi:10.1016/s1074-7613(03)00029-3

Cited by 253 publications

(276 citation statements)

References 55 publications

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“…Loss of these interactions led to loss of MZB cells in many mouse strains 21,25,26,33 . Secondly, Notch2 ligation by Dll1 expressed on stromal cells is required for MZB development [2][3][4][5][6][7][8][9][10][11][12][13] , and maintenance of MZB identity 12,34 . Thirdly, the quality and the strength of the BCR repertoire determine whether positive selection of immature B cells by self ligands or microbiome derived ligands leads to deletion, FoB cell or MZB development [14][15][16]35 .…”

Section: Discussionmentioning

confidence: 99%

“…B1 cells derive from fetal progenitors and react to a restricted set of microbial ligands in a T cell-independent (TI) manner in serosal cavities and spleen 1 NF-B signaling emanating from the BAFF receptor [2][3][4][5][6][7][8][9][10][11][12][13] . The quality of B cell antigen receptor (BCR) signals during positive selection of B cell precursors in the spleen is equally important in B cell fate decisions [14][15][16] , and it was proposed that weak or strong BCR signals might render cells receptive or resistant to Notch instruction 17,18 .…”

Section: Introductionmentioning

confidence: 99%

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Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10

et al. 2017

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2 Notch2 and B cell antigen receptor (BCR) signaling determine if transitional B cells become marginal zone B (MZB) or follicular B (FoB) cells in the spleen, but it isunknown how these pathways are related. We generated Taok3 equally important in B cell fate decisions [14][15][16] , and it was proposed that weak or strong BCR signals might render cells receptive or resistant to Notch instruction 17,18 . Yet how BCR repertoire or signaling controls Notch responsiveness is currently poorly understood.The Ste20 family kinases are serine-threonine kinases that participate in a variety of signaling pathways triggered by cellular stress 19,20 . The Tao kinase subfamily has three members in mammals (TAOK1, also known as proteins MAP3K16, PSK2 or MARKK; TAOK2 (MAP3K17, PSK1) and TAOK3 (MAP3K18, JIK or DPK)), whose function is largely unknown. Here, we generated Taok3 -/-mice and found that these mice lacked MZB cells, whereas FoB cells were intact. By carefully unraveling the molecular mechanism of this deficiency we have discovered how BCR signaling intersects with Notch signaling in immature transitional B cells undergoing positive selection. RESULTS 4 Taok3 -/-mice lack MZB cellsIn wild-type mice, the expression of mRNA for Taok3 was predominantly found in bone marrow and immune tissues like spleen, thymus and lymph nodes, but also in lung and gut (Fig. 1a). To gain insight into the biology of Taok3, we generated Taok3 -/-mice ( Supplementary Fig. 1a-e). Overall there was no difference in the cellularity of the various lymphoid organs in 6-12 week old mice (Supplementary Fig. 1f). In the spleen, there were no gross differences in the percentage of eosinophils, monocytes, natural killer (NK) cells and NKT cells between Taok3 -/-and wild-type mice, yet there was a consistent reduction in the amount of CD11c + dendritic cells in Taok3 -/-mice (Fig. 1b).There was a small yet consistent increase in the percentage of Ly6G + granulocytes in the spleen of Taok3 -/-mice. The distribution of CD3 + T cells and CD19 + B cells was comparable, yet there was a 25-30% reduction in the amount of CD8 + T cells (Fig. 1c). (Fig. 1d-f).Histological examination of the spleen revealed that the characteristic rim of IgM + CD1d + MZB cells separated from the IgM lo B cell follicles by the marginal sinus was absent in Taok3 -/-mice (Fig. 1g). Resident marginal zone metallophillic macrophages (MMM, expressing CD169) that line the marginal sinus were present and correctly localized in Taok3 -/-mice (Fig. 1h) (Fig. 1h). Collectively, Taok3 -/-mice lack MZB cells without compensatory alterations in other B cell subsets. Humoral immune response of Taok3 -/-miceThe baseline serum concentration of immunoglobulins (Ig) was comparable to wild-type, with a tendency for increased IgG3 in Taok3 -/-mice (Supplementary Fig 2) Fig. 1i and Supplementary Fig 2 ). The intact TNPspecific Ig response as not due to compensatory increase in recirculating MZB cells outside the spleen (data not shown). B1 B cells can also respond to TNP-Ficoll antigen, in the com...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10

et al. 2017

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“…Inactivation of the repressor activity of RBP-J by Notch signaling promotes marginal zone B cell formation, whereas the Notchantagonizing protein MINT prevents it [40,41]. Lack of marginal zone B cells is also observed upon deficiencies of Pyk-2, DOCK-2 and Lsc, three proteins implicated in migratory responses to chemokines [34,[42][43][44], and of the transcriptional co-activator BOB.1/OBF.1/OCA-B [45].…”

Section: Discussionmentioning

confidence: 99%

The anti‐apoptotic factor Bcl‐2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF

et al. 2004

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The TNF family ligand B cell-activating factor (BAFF, BLyS, TALL-1) is an essential factor for B cell development. BAFF binds to three receptors, BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA), but only BAFF-R is required for successful survival and maturation of splenic B cells. To test whether the effect of BAFF is due to the up-regulation of anti-apoptotic factors, TACI-Ig-transgenic mice, in which BAFF function is inhibited, were crossed with transgenic mice expressing FLICE-inhibitory protein (FLIP) or Bcl-2 in the B cell compartment. FLIP expression did not rescue B cells, while enforced Bcl-2 expression restored peripheral B cells and the ability to mount T-dependent antibody responses. However, many B cells retained immaturity markers and failed to express normal amounts of CD21. Marginal zone B cells were not restored and the Tindependent IgG3, but not IgM, response was impaired in the TACI-Ig×Bcl-2 mice. These results suggest that BAFF is required not only to inhibit apoptosis of maturating B cells, but also to promote differentiation events, in particular those leading to the generation of marginal zone B cells.

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“…MINTdeficient mice are embryonic lethal, due to defective heart, pancreas and hematopoietic development [82]. [85].…”

Section: Epigenetic Regulation Of Notch Target Genesmentioning

confidence: 99%

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Borggrefe

Oswald

2009

Cell. Mol. Life Sci.

584

499

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. The Notch gene encodes a transmembrane receptor that gave the name to the evolutionary highly conserved Notch signaling cascade. It plays a pivotal role in the regulation of many fundamental cellular processes such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. After specific ligand binding, the intracellular part of the Notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor RBP-J. In the absence of activated Notch, RBP-J represses Notch target genes by recruiting a corepressor complex. Here, we review Notch signaling with a focus on gene regulatory events at Notch target genes. This is of utmost importance to understand Notch signaling since certain RBP-J associated cofactors and particular epigenetic marks determine the specificity of Notch target gene expression in different cell types. We subsequently summarize the current knowledge about Notch target genes and the physiological significance of Notch signaling in development and cancer.

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Regulation of Marginal Zone B Cell Development by MINT, a Suppressor of Notch/RBP-J Signaling Pathway

Cited by 253 publications

References 55 publications

Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10

Transitional B cells commit to marginal zone B cell fate by Taok3-mediated surface expression of ADAM10

The anti‐apoptotic factor Bcl‐2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF

The Notch signaling pathway: Transcriptional regulation at Notch target genes

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