Assembling a gene regulatory network for specification of the B cell fate.
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.
Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA.
Kay L
KL
Medina
Jagan M R
JM
Pongubala
Karen L
KL
Reddy
David W
DW
Lancki
Rodney
R
Dekoter
Matthias
M
Kieslinger
Rudolf
R
Grosschedl
Harinder
H
Singh
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D001665:Binding Sites; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005816:Genetic Complementation Test; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D051757:PAX5 Transcription Factor; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D004268:DNA-Binding Proteins; D051757:PAX5 Transcription Factor; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C081976:EBF1 protein, human; C497282:Pax5 protein, mouse