title: LRF-mediated Dll4 repression in erythroblasts is necessary for hematopoietic stem cell maintenance.
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.
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
authors.forename: Sung-Uk
authors.initials: SU
authors.lastname: Lee
authors.forename: Manami
authors.initials: M
authors.lastname: Maeda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Sierra Min
authors.initials: SM
authors.lastname: Li
authors.forename: Anne
authors.initials: A
authors.lastname: Wilson
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Jubb
authors.forename: Nagisa
authors.initials: N
authors.lastname: Sakurai
authors.forename: Lihong
authors.initials: L
authors.lastname: Weng
authors.forename: Emma
authors.initials: E
authors.lastname: Fiorini
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Minhong
authors.initials: M
authors.lastname: Yan
authors.forename: H Robson
authors.initials: HR
authors.lastname: Macdonald
authors.forename: Ching-Cheng
authors.initials: CC
authors.lastname: Chen
authors.forename: Takahiro
authors.initials: T
authors.lastname: Maeda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D060833:Cellular Microenvironment / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004900:Erythroblasts / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D014157:Transcription Factors; C117093:Zbtb7a protein, mouse