TY - JOUR
T1 - Hoxa9 and Flt3 signaling synergistically regulate an early checkpoint in lymphopoiesis
AU - Gwin, Kimberly A.
AU - Shapiro, Mariya B.
AU - Dolence, Joseph J.
AU - Huang, Zhixin L.
AU - Medina, Kay L.
PY - 2013/7/15
Y1 - 2013/7/15
N2 - Hoxa9 and Flt3 signaling are individually important for the generation of lymphoid lineage precursors from multipotent hematopoietic progenitors (MPP) in bone marrow. Mice deficient for Hoxa9, Flt3, or Flt3 ligand (FL) have reduced numbers of lymphoidprimed multipotential progenitors (LMPP), common lymphoid progenitors (CLP), and B/T cell precursors. Hoxa9 regulates lymphoid development, in part, through transcriptional regulation of Flt3. However, it was unclear whether Hoxa9 has functions in lymphopoiesis independent of, or alternatively, synergistically with Flt3 signaling. In this study, we show that Hoxa9-/-Flt3l-/- mice have more severe deficiencies in all B lineage cells, CLP, LMPP, and total Flt3+ MPP in bone marrow than the single knockouts. Although LMPP and Flt3+ CLP contain precursors for NK and dendritic cell lineage cells, no deficiencies in these lineages beyond that in Flt3l-/- mice was found. Thymocyte cellularity was significantly reduced in the compound knockout, although peripheral T cell numbers mirrored Flt3l-/- mice. Analysis of the hematopoietic progenitor compartment revealed elevated numbers of CD150+hiCD34-CD41+ myeloid-biased stem cells in Hoxa9-/-Flt3l-/- mice. In contrast, CD150- MPP enriched for lymphoid potential were synergistically reduced, suggesting Hoxa9 and Flt3 signaling function coordinately to regulate lymphopoiesis at a very early stage. Real-time PCR analysis of CD150-Flt3+ cells from wild-type control, Hoxa9-/-, and Flt3l-/- single knockouts revealed decreased lymphoid transcripts, corroborating the importance of these regulators in lymphoid development. Taken together, these studies reveal a very early checkpoint in lymphopoiesis dependent on the combinatorial activities of Hoxa9 function and Flt3 signaling.
AB - Hoxa9 and Flt3 signaling are individually important for the generation of lymphoid lineage precursors from multipotent hematopoietic progenitors (MPP) in bone marrow. Mice deficient for Hoxa9, Flt3, or Flt3 ligand (FL) have reduced numbers of lymphoidprimed multipotential progenitors (LMPP), common lymphoid progenitors (CLP), and B/T cell precursors. Hoxa9 regulates lymphoid development, in part, through transcriptional regulation of Flt3. However, it was unclear whether Hoxa9 has functions in lymphopoiesis independent of, or alternatively, synergistically with Flt3 signaling. In this study, we show that Hoxa9-/-Flt3l-/- mice have more severe deficiencies in all B lineage cells, CLP, LMPP, and total Flt3+ MPP in bone marrow than the single knockouts. Although LMPP and Flt3+ CLP contain precursors for NK and dendritic cell lineage cells, no deficiencies in these lineages beyond that in Flt3l-/- mice was found. Thymocyte cellularity was significantly reduced in the compound knockout, although peripheral T cell numbers mirrored Flt3l-/- mice. Analysis of the hematopoietic progenitor compartment revealed elevated numbers of CD150+hiCD34-CD41+ myeloid-biased stem cells in Hoxa9-/-Flt3l-/- mice. In contrast, CD150- MPP enriched for lymphoid potential were synergistically reduced, suggesting Hoxa9 and Flt3 signaling function coordinately to regulate lymphopoiesis at a very early stage. Real-time PCR analysis of CD150-Flt3+ cells from wild-type control, Hoxa9-/-, and Flt3l-/- single knockouts revealed decreased lymphoid transcripts, corroborating the importance of these regulators in lymphoid development. Taken together, these studies reveal a very early checkpoint in lymphopoiesis dependent on the combinatorial activities of Hoxa9 function and Flt3 signaling.
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U2 - 10.4049/jimmunol.1203294
DO - 10.4049/jimmunol.1203294
M3 - Article
C2 - 23772038
AN - SCOPUS:84880117815
SN - 0022-1767
VL - 191
SP - 745
EP - 754
JO - Journal of Immunology
JF - Journal of Immunology
IS - 2
ER -