Ebf1-mediated down-regulation of Id2 and Id3 is essential for specification of the B cell lineage.
Gene knockout experiments in mice have suggested a hierarchical model of early B cell commitment wherein E2A proteins (E47 and E12) activate early B cell factor (Ebf1), which in turn activates expression of the B cell commitment factor, Pax5. In IL-7 receptor alpha (IL-7Ralpha) knockout mice, B cell development is blocked before B-lineage commitment at the prepro-B cell stage in adult animals. In IL-7Ralpha(-/-) prepro-B cells, E47 is expressed and yet is insufficient to transcriptionally activate the putative downstream target gene, Ebf1. In this study, we show that further increases of E47 expression in IL-7Ralpha(-/-) prepro-B cells fails to activate Ebf1, but rather leads to a dramatic induction of the E2A inhibitory factors, Id2 and Id3. In contrast, enforced expression of Ebf1 in IL-7Ralpha(-/-) bone marrow potently down-regulates Id2 and Id3 mRNA expression and restores B cell differentiation in vivo. Down-regulation of both Id2 and Id3 during B cell specification is essential in that overexpression of either Id2 or Id3 in wild-type bone marrow blocks B cell specification at the prepro-B cell stage. Collectively, these studies suggest a model where Ebf1 induction specifies the B cell fate by dramatically increasing activity of E47 at the posttranslational level.
Thal
Melissa A
MA
Department of Microbiology, The University of Alabama-Birmingham, Birmingham, AL 35294, USA.
Carvalho
Thiago L
TL
He
Ti
T
Kim
Hyung-Gyoon
HG
Gao
Hua
H
Hagman
James
J
Klug
Christopher A
CA
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D001853:Bone Marrow; D002454:Cell Differentiation; D019070:Cell Lineage; D015536:Down-Regulation; D005786:Gene Expression Regulation; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics* / Q000502:physiology; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics* / Q000502:physiology; D015851:Interleukin-7 / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D054448:Precursor Cells, B-Lymphoid; D012333:RNA, Messenger / Q000032:analysis; D020395:Receptors, Interleukin-7 / Q000172:deficiency*; D051820:TCF Transcription Factors / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D058125:Transcription Factor 7-Like 1 Protein
C489921:Ebf1 protein, mouse; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D015851:Interleukin-7; D012333:RNA, Messenger; D020395:Receptors, Interleukin-7; D051820:TCF Transcription Factors; C544913:Tcf7l1 protein, mouse; D015534:Trans-Activators; D058125:Transcription Factor 7-Like 1 Protein; C415350:interleukin-7 receptor, alpha chain; C067679:Idb3 protein, mouse