Lunatic and Manic Fringe Cooperatively Enhance Marginal Zone B Cell Precursor Competition for Delta-like 1 in Splenic Endothelial Niches
ABSTRACT Notch2 activation induced by Delta-like-1 (DL1) drives development of splenic marginal zone (MZ) B cells, an innate-like lineage that protects against sepsis. DL1 interacts with Notch2 weakly, but it is not known whether enhancement of DL1-induced Notch2 activation by Fringe glycosyltransferases is important for MZ B cell development. Furthermore, DL1-expressing cells that promote MZ B cell development have not been identified. We show that Lunatic Fringe (Lfng) and Manic Fringe (Mfng) cooperatively enhanced the DL1-Notch2 interaction to promote MZ B cell development. We also identified radio-resistant red pulp endothelial cells in the splenic MZ that express high amounts of DL1 and promoted MZ B generation. Finally, MZ B cell precursor competition for DL1 homeostatically regulated entry into the MZ B cell pool. Our study has revealed that the Fringe-Notch2 interaction has important functions in vivo and provides insights into mechanisms regulating MZ B cell development.
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ABSTRACT: The Consortium for Functional Glycomics (CFG) was a large research initiative providing networking and resources for investigators studying the role of glycans and glycan-binding proteins in health and disease. Starting in 2001, six scientific cores were established to generate data, materials, and new technologies. By the end of funding in 2011, the Mouse Phenotype Core (MPC) submitted data to a website from the phenotype screen of thirty-six mutant mouse strains deficient in a gene for either a glycan-binding protein (GBP) or glycosyltransferase (GT). Each mutant strain was allotted three months for analysis and screened by standard phenotype assays used in the fields of immunology, histology, hematology, coagulation, serum chemistry, metabolism, and behavior. Twenty of the deficient mouse strains had been studied in other laboratories, and additional tests were performed on these strains to confirm previous observations and discover new data. The CFG constructed sixteen new homozygous mutant mouse strains and completed the initial phenotype screen of the majority of these new mutant strains. In total more than three hundred phenotype changes were observed, but considering the over one hundred assays performed on each strain, most of the phenotypes were unchanged. Phenotype differences include abnormal testis morphology in GlcNAcT9 and Siglec-H deficient mice, and lethality in Pomgnt1 deficient mice. The numerous altered phenotypes discovered, along with the consideration of the significant findings of normality, will provide a platform for future characterization to understand of the important role of glycans and GBPs in the mechanisms of health and disease.Glycobiology 10/2012; DOI:10.1093/glycob/cws150 · 3.75 Impact Factor
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ABSTRACT: Dendritic cells (DCs) in tissues and lymphoid organs comprise distinct functional subsets that differentiate in situ from circulating progenitors. Tissue-specific signals that regulate DC subset differentiation are poorly understood. We report that DC-specific deletion of the Notch2 receptor caused a reduction of DC populations in the spleen. Within the splenic CD11b(+) DC subset, Notch signaling blockade ablated a distinct population marked by high expression of the adhesion molecule Esam. The Notch-dependent Esam(hi) DC subset required lymphotoxin beta receptor signaling, proliferated in situ, and facilitated CD4(+) T cell priming. The Notch-independent Esam(lo) DCs expressed monocyte-related genes and showed superior cytokine responses. In addition, Notch2 deletion led to the loss of CD11b(+)CD103(+) DCs in the intestinal lamina propria and to a corresponding decrease of IL-17-producing CD4(+) T cells in the intestine. Thus, Notch2 is a common differentiation signal for T cell-priming CD11b(+) DC subsets in the spleen and intestine.Immunity 11/2011; 35(5):780-91. DOI:10.1016/j.immuni.2011.08.013 · 19.75 Impact Factor
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ABSTRACT: The hemangioblast hypothesis has been hotly debated for over a century. Hemangioblasts are defined as multipotent cells that can give rise to both hematopoietic cells and endothelial cells. The existence of hemangioblasts has now been confirmed and many important molecules and several signaling pathways are involved in their generation and differentiation. Fibroblast growth factor, renin-angiotensin system and runt-related transcription factor 1 (Runx1) direct the formation of hemangioblasts through highly selective gene expression patterns. On the other hand, the hemogenic endothelium theory and a newly discovered pattern of hematopoietic/endothelial differentiation make the genesis of hemangioblasts more complicated. But how hemangioblasts are formed and how hematopoietic cells or endothelial cells are derived from remains largely unknown. Here we summarize the current knowledge of the signaling pathways and molecules involved in hemangioblast development and suggest some future clinical applications.The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 04/2011; 294(4):580-8. DOI:10.1002/ar.21360 · 1.53 Impact Factor