TY - JOUR
T1 - Assembling a gene regulatory network for specification of the B cell fate
AU - Medina, Kay L.
AU - Pongubala, Jagan M.R.
AU - Reddy, Karen L.
AU - Lancki, David W.
AU - DeKoter, Rodney
AU - Kieslinger, Matthias
AU - Grosschedl, Rudolf
AU - Singh, Harinder
N1 - Funding Information:
We thank P. Kincade for the biotinylated IL-7R antibody and M. Busslinger for the Pax-5 cDNA as well as Pax-5 −/− pro-B cells. We thank members of the Singh lab for thoughtful discussions and comments on the manuscript and T. Graf and B. Kee for sharing unpublished results. K.L.M. is supported by the Irvington Institute for Immunological Research and H.S. is an Investigator of the Howard Hughes Medical Institute.
PY - 2004/10
Y1 - 2004/10
N2 - The generation of B lymphocyte precursors is dependent on the combinatorial action of the transcription factors PU.1, Ikaros, E2A, EBF, and Pax-5. Loss of PU.1 results in a severe reduction in Flk2+, IL-7R+ lymphoid progenitors as well as impaired expression of EBF and Pax-5. Restoration of EBF expression facilitates rapid generation of pro-B cells from PU.1-/- progenitors. Molecular analysis suggests that PU.1 directly participates in regulation of the EBF gene. Although PU.1 is dispensable for expression of most early B lineage genes, it is required for CD45R/B220. Using EBF-/- mutant progenitors, we show that EBF induces Pax-5 and the early program of B lineage gene expression. Importantly, Pax-5 does not rescue B cell development from either PU.1-/- or EBF-/- progenitors. Pax-5 expression and function are contingent on EBF. Based on these results, we propose a hierarchical regulatory network for specification and commitment to the B cell fate.
AB - The generation of B lymphocyte precursors is dependent on the combinatorial action of the transcription factors PU.1, Ikaros, E2A, EBF, and Pax-5. Loss of PU.1 results in a severe reduction in Flk2+, IL-7R+ lymphoid progenitors as well as impaired expression of EBF and Pax-5. Restoration of EBF expression facilitates rapid generation of pro-B cells from PU.1-/- progenitors. Molecular analysis suggests that PU.1 directly participates in regulation of the EBF gene. Although PU.1 is dispensable for expression of most early B lineage genes, it is required for CD45R/B220. Using EBF-/- mutant progenitors, we show that EBF induces Pax-5 and the early program of B lineage gene expression. Importantly, Pax-5 does not rescue B cell development from either PU.1-/- or EBF-/- progenitors. Pax-5 expression and function are contingent on EBF. Based on these results, we propose a hierarchical regulatory network for specification and commitment to the B cell fate.
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U2 - 10.1016/j.devcel.2004.08.006
DO - 10.1016/j.devcel.2004.08.006
M3 - Article
C2 - 15469848
AN - SCOPUS:5044249424
SN - 1534-5807
VL - 7
SP - 607
EP - 617
JO - Developmental Cell
JF - Developmental Cell
IS - 4
ER -