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Medina, K.L.* ; Pongubala, J.M.* ; Reddy, K.L.* ; Lancki, D.W.* ; Dekoter, R.* ; Kieslinger, M.* ; Grosschedl, R.* ; Singh, H.*

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

Dev. Cell 7, 607-617 (2004)

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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.

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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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