A Flt3- and Ras-dependent pathway primes B cell development by inducing a state of IL-7 responsiveness.
Ras plays an important role in B cell development. However, the stage at which Ras governs B cell development remains unclear. Moreover, the upstream receptors and downstream effectors of Ras that govern B cell differentiation remain undefined. Using mice that express a dominant-negative form of Ras, we demonstrate that Ras-mediated signaling plays a critical role in the development of common lymphoid progenitors. This developmental block parallels that found in flt3(-/-) mice, suggesting that Flt3 is an important upstream activator of Ras in early B cell progenitors. Ras inhibition impaired proliferation of common lymphoid progenitors and pre-pro-B cells but not pro-B cells. Rather, Ras promotes STAT5-dependent pro-B cell differentiation by enhancing IL-7Ralpha levels and suppressing socs2 and socs3 expression. Our results suggest a model in which Flt3/Ras-dependent signals play a critical role in B cell development by priming early B cell progenitors for subsequent STAT5-dependent B cell differentiation.
Li
Lin-Xi
LX
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Goetz
Christine A
CA
Katerndahl
Casey D S
CD
Sakaguchi
Nobuo
N
Farrar
Michael A
MA
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D055879:Gene Knock-In Techniques; D006801:Humans; D015851:Interleukin-7 / Q000502:physiology*; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D050799:STAT5 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051941:fms-Like Tyrosine Kinase 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
D015851:Interleukin-7; D050799:STAT5 Transcription Factor; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; D018631:ras Proteins