Developmentally regulated expression of MEF2C limits the response to BCR engagement in transitional B cells.
Transitional and naïve mature peripheral B cells respond very differently to B-cell receptor (BCR) cross-linking. While transitional B cells undergo apoptosis upon BCR engagement, mature B cells survive and proliferate. This differential response correlates with the capacity of mature, but not transitional B cells to transcribe genes that promote cell survival and proliferation, including those encoding c-Myc and the Bcl-2 family members Bcl-xL and A1. We recently demonstrated that transitional B cells fail to assemble transcriptional machinery at the promoter region of these target genes despite equivalent cytoplasmic signaling and nuclear translocation of key transcription factors including NF-κB and nuclear factor of activated T cells (NFAT). The transcription factor myocyte enhancer factor-2C (MEF2C) is regulated by both calcineurin and mitogen-activated protein kinase signaling pathways, and is essential for proliferation and survival downstream of BCR engagement in mature B cells. In this work, we demonstrate that transitional B cells have intrinsically low levels of MEF2C protein and DNA-binding activity, and that this developmental difference in MEF2C expression is functionally significant. Forced expression of MEF2C in transitional B cells promoted cell survival, proliferation, and upregulation of pro-survival genes. Thus, low MEF2C expression limits transitional B-cell responsiveness to BCR engagement before these cells reach maturity.
Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA, USA.
Sarah F
SF
Andrews
Xuezhi
X
Dai
Byoung Y
BY
Ryu
Tod
T
Gulick
Bindu
B
Ramachandran
David J
DJ
Rawlings
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D049109:Cell Proliferation; D002470:Cell Survival; D018507:Gene Expression Regulation, Developmental; D064326:MEF2 Transcription Factors; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018006:Myogenic Regulatory Factors / Q000032:analysis / Q000235:genetics*; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D008565:Membrane Proteins; D018006:Myogenic Regulatory Factors; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell