TY - JOUR
T1 - Threshold levels of Flt3-ligand are required for the generation and survival of lymphoid progenitors and B-cell precursors
AU - Dolence, Joseph J.
AU - Gwin, Kimberly
AU - Frank, Elena
AU - Medina, Kay L.
PY - 2011/2
Y1 - 2011/2
N2 - 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 Flt3low LSK+ cells exhibited increased Annexin V staining. Together, these data suggest that Flt3 signaling initiates a cascade of events in Flt3low precursors that promote the survival of LHP from which BCP are derived.
AB - 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 Flt3low LSK+ cells exhibited increased Annexin V staining. Together, these data suggest that Flt3 signaling initiates a cascade of events in Flt3low precursors that promote the survival of LHP from which BCP are derived.
KW - Apoptosis
KW - B-cell development
KW - Cell differentiation
KW - Flt3-ligand
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U2 - 10.1002/eji.201040710
DO - 10.1002/eji.201040710
M3 - Article
C2 - 21268003
AN - SCOPUS:78851471689
SN - 0014-2980
VL - 41
SP - 324
EP - 334
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 2
ER -