51. LRF-mediated Dll4 repression in erythroblasts is necessary for hematopoietic stem cell maintenance
- Author
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Nagisa Sakurai, Takahiro Maeda, Sung-Uk Lee, Manami Maeda, Freddy Radtke, H. Robson MacDonald, Adrian M. Jubb, Minhong Yan, Ching-Cheng Chen, Sierra Min Li, Anne Wilson, Lihong Weng, Emma Fiorini, and Yuichi Ishikawa
- Subjects
Time Factors ,Erythroblasts ,Hematopoiesis and Stem Cells ,Cellular differentiation ,T-Lymphocytes ,Biochemistry ,Transcriptome ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Receptor, Notch1 ,Bone Marrow Transplantation ,Oligonucleotide Array Sequence Analysis ,Mice, Knockout ,0303 health sciences ,Reverse Transcriptase Polymerase Chain Reaction ,Intracellular Signaling Peptides and Proteins ,Hematopoietic stem cell ,hemic and immune systems ,Cell Differentiation ,Hematology ,Immunohistochemistry ,Cell biology ,DNA-Binding Proteins ,Leukemia ,Haematopoiesis ,medicine.anatomical_structure ,Cellular Microenvironment ,030220 oncology & carcinogenesis ,Stem cell ,Signal Transduction ,Immunology ,Bone Marrow Cells ,Biology ,03 medical and health sciences ,medicine ,Animals ,Transcription factor ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Calcium-Binding Proteins ,Membrane Proteins ,Cell Biology ,medicine.disease ,Hematopoietic Stem Cells ,Mice, Inbred C57BL ,Bone marrow ,Transcription Factors - Abstract
Hematopoietic stem cells (HSCs) are the most primitive cells in the hematopoietic system and are under tight regulation for self-renewal and differentiation. Notch signals are essential for the emergence of definitive hematopoiesis in mouse embryos and are critical regulators of lymphoid lineage fate determination. However, it remains unclear how Notch regulates the balance between HSC self-renewal and differentiation in the adult bone marrow (BM). Here we report a novel mechanism that prevents HSCs from undergoing premature lymphoid differentiation in BM. Using a series of in vivo mouse models and functional HSC assays, we show that leukemia/lymphoma related factor (LRF) is necessary for HSC maintenance by functioning as an erythroid-specific repressor of Delta-like 4 (Dll4) expression. Lrf deletion in erythroblasts promoted up-regulation of Dll4 in erythroblasts, sensitizing HSCs to T-cell instructive signals in the BM. Our study reveals novel cross-talk between HSCs and erythroblasts, and sheds a new light on the regulatory mechanisms regulating the balance between HSC self-renewal and differentiation. (Blood. 2013;121(6):918-929)
- Published
- 2013
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