Lack of nuclear factor-kappa B2/p100 causes a RelB-dependent block in early B lymphopoiesis.
Nuclear factor-kappaB (NF-kappaB) transcription factors regulate B-cell development and survival. However, whether they also have a role during early steps of B-cell differentiation is largely unclear. Here, we show that constitutive activation of the alternative NF-kappaB pathway in p100(-/-) knockin mice resulted in a block of early B-cell development at the transition from the pre-pro-B to the pro-B-cell stage due to enhanced RelB activity. Expression of the essential B-cell transcription factors EBF and in particular Pax5 was reduced in p100(-/-) B-cell precursors in a RelB-dependent manner, resulting in reduced mRNA levels of B lineage-specific genes. Moreover, enhanced RelB function in p100(-/-) B-cell precursors was accompanied by increased expression of B lineage-inappropriate genes, such as C/EBP alpha, correlating with a markedly increased myeloid differentiation potential of p100(-/-) progenitor B cells. Ectopic expression of Pax5 in hematopoietic progenitors restored early B-cell development in p100(-/-) bone marrow, suggesting that impaired early B lymphopoiesis in mice lacking the p100 inhibitor may be due to down-regulation of Pax5 expression. Thus, tightly controlled p100 processing and RelB activation is essential for normal B lymphopoiesis and lymphoid/myeloid lineage decision in bone marrow.
Guo
Feng
F
Research Group Immunology, Leibniz-Institute for Age Research-Fritz-Lipmann-Institute, Jena, Germany.
Tänzer
Simone
S
Busslinger
Meinrad
M
Weih
Falk
F
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D001853:Bone Marrow; D019070:Cell Lineage; D038041:Lymphopoiesis; D051379:Mice; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000172:deficiency / Q000502:physiology*; D051757:PAX5 Transcription Factor / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D051841:Transcription Factor RelB / Q000502:physiology*
C489921:Ebf1 protein, mouse; D052003:NF-kappa B p52 Subunit; C498207:Nfkb2 protein, mouse; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D015534:Trans-Activators; D051841:Transcription Factor RelB