期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 214, 期 7, 页码 2041-2057出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20160852
关键词
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资金
- Medical Research Council [G0900161/1, MR/P000843/1]
- Biotechnology and Biological Sciences Research Council [BB/I026324/1]
- Wellcome Trust [WT094255MF]
- Great Ormond Street Hospital Children's Charity
- National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust [ormbrc-2012-1]
- University College London
- National Institutes of Health Research (NIHR) [ormbrc-2012-1] Funding Source: National Institutes of Health Research (NIHR)
- BBSRC [BB/I026324/1] Funding Source: UKRI
- MRC [MR/P000843/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I026324/1] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1297] Funding Source: researchfish
- Medical Research Council [MR/P000843/1, 1212180] Funding Source: researchfish
Before birth, B cells develop in the fetal liver (FL). In this study, we show that Gli3 activity in the FL stroma is required for B cell development. In the Gli3-deficient FL, B cell development was reduced at multiple stages, whereas the Sonic hedgehog (Hh [Shh])-deficient FL showed increased B cell development, and Gli3 functioned to repress Shh transcription. Use of a transgenic Hh-reporter mouse showed that Shh signals directly to developing B cells and that Hh pathway activation was increased in developing B cells from Gli3-deficient FLs. RNA sequencing confirmed that Hh-mediated transcription is increased in B-lineage cells from Gli3-deficient FL and showed that these cells expressed reduced levels of B-lineage transcription factors and B cell receptor (BCR)/pre-BCR-signaling genes. Expression of the master regulators of B cell development Ebf1 and Pax5 was reduced in developing B cells from Gli3-deficient FL but increased in Shh-deficient FL, and in vitro Shh treatment or neutralization reduced or increased their expression, respectively.
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