Core binding factors are necessary for natural killer cell development and cooperate with Notch signaling during T-cell specification.
CBFbeta is the non-DNA binding subunit of the core binding factors (CBFs). Mice with reduced CBFbeta levels display profound, early defects in T-cell but not B-cell development. Here we show that CBFbeta is also required at very early stages of natural killer (NK)-cell development. We also demonstrate that T-cell development aborts during specification, as the expression of Gata3 and Tcf7, which encode key regulators of T lineage specification, is substantially reduced, as are functional thymic progenitors. Constitutively active Notch or IL-7 signaling cannot restore T-cell expansion or differentiation of CBFbeta insufficient cells, nor can overexpression of Runx1 or CBFbeta overcome a lack of Notch signaling. Therefore, the ability of the prethymic cell to respond appropriately to Notch is dependent on CBFbeta, and both signals converge to activate the T-cell developmental program.
Guo
Yalin
Y
Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755, USA.
Maillard
Ivan
I
Chakraborti
Sankhamala
S
Rothenberg
Ellen V
EV
Speck
Nancy A
NA
D000818:Animals; D019070:Cell Lineage; D050658:Core Binding Factor beta Subunit / Q000172:deficiency / Q000502:physiology*; D050990:GATA3 Transcription Factor / Q000172:deficiency; D051538:Hepatocyte Nuclear Factor 1-alpha; D007694:Killer Cells, Natural / Q000166:cytology*; D038041:Lymphopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction; D051822:T Cell Transcription Factor 1 / Q000172:deficiency; D013601:T-Lymphocytes / Q000166:cytology*
C493693:Cbfb protein, mouse; D050658:Core Binding Factor beta Subunit; D050990:GATA3 Transcription Factor; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D051880:Receptors, Notch; D051822:T Cell Transcription Factor 1