Assembling a gene regulatory network for specification of the B cell fate

Kay L. Medina, Jagan M.R. Pongubala, Karen L. Reddy, David W. Lancki, Rodney DeKoter, Matthias Kieslinger, Rudolf Grosschedl, Harinder Singh

Research output: Contribution to journalArticlepeer-review

189 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)607-617
Number of pages11
JournalDevelopmental Cell
Volume7
Issue number4
DOIs
StatePublished - Oct 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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