Threshold levels of Flt3-ligand are required for the generation and survival of lymphoid progenitors and B-cell precursors.
The generation of B-cell precursors (BCP) from lymphohematopoietic progenitors (LHP) in bone marrow is dependent on signals provided by the receptor tyrosine kinase Flt3 and its ligand, Flt3-ligand (FL). Mice deficient in FL exhibit striking reductions in LHP and BCP. Currently, the mechanism by which Flt3 regulates lymphoid lineage/B-cell development is unknown. Here, we show that haploinsufficiency of FL (FL(+/) (-) ) reduced the numbers of LHP, common lymphoid progenitors, and pro-B cells, suggesting that FL levels set a threshold for B lymphopoiesis. Limiting dilution analysis confirmed reduced BCP frequency in FL(+/) (-) mice. Real-time PCR of LHP from FL(+/) (-) animals showed increased transcripts of the B lineage inhibitor id1. However, targeted deletion of id1 did not restore the lymphoid/B lineage deficiencies in FL(-/-) mice, supporting Id1-independent mechanisms. BrdU incorporation studies established that FL is not essential for the proliferation of Flt3(+) multipotential progenitors. Analysis of FL(-/-) progenitors expressing low levels of Flt3 revealed decreased levels of the pro-survival factor Mcl1. Consequently, the Flt3(+) LHP progeny of Flt3(low) LSK(+) cells exhibited increased Annexin V staining. Together, these data suggest that Flt3 signaling initiates a cascade of events in Flt3(low) precursors that promote the survival of LHP from which BCP are derived.
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Joseph J
JJ
Dolence
Kimberly
K
Gwin
Elena
E
Frank
Kay L
KL
Medina
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002452:Cell Count; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000235:genetics; D057895:Haploinsufficiency / Q000276:immunology; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics; D054503:Lymphoid Progenitor Cells / Q000166:cytology* / Q000378:metabolism; D038041:Lymphopoiesis / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
D018398:Homeodomain Proteins; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; C084881:flt3 ligand protein; C064658:RAG-1 protein; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3
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