BMP4 acts upstream of FGF in modulating thymic stroma and regulating thymopoiesis.
Thymocyte development is a non-cell-autonomous process that requires signals provided by the thymic stroma. Bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) derived from thymic stroma have been implicated as possible regulators of T-cell development. Using thymic organ culture, this study demonstrates that both BMP4 and FGF7/FGF10 arrest early T-cell development at the CD4-CD8-CD44+CD25- (double-negative 1 [DN1]) population and at the CD4-CD8- double-negative (DN) to CD4+CD8+ double-positive (DP) transition in a stromal compartment-dependent manner. Furthermore, BMP4 functions upstream of FGF7/FGF10, as the effects of BMP can be suppressed by cotreatment with an FGF receptor antagonist. BMP4 also acts directly on the thymic stroma to up-regulate the stroma-specific transcription factor Foxn1 and stroma-expressed chemokines. Taken together, the data in this report demonstrate that BMP acts upstream of FGF in the regulation of early T-cell development and that BMP4 acts primarily through the thymic stroma, thereby altering the thymic microenvironment and affecting thymopoiesis.
Tsai
Peter T
PT
Molecular Biology Institute, Department of Molecular and Medical Pharmacology, and the Howard Hughes Medical Institute, UCLA School of Medicine, Los Angeles, CA 90095-1735, USA.
Lee
Robert A
RA
Wu
Hong
H
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D018925:Chemokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000502:physiology*; D051858:Forkhead Transcription Factors; D038041:Lymphopoiesis; D051379:Mice; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D018925:Chemokines; D004268:DNA-Binding Proteins; C496464:Fgf10 protein, mouse; C496454:Fgf7 protein, mouse; D051526:Fibroblast Growth Factor 10; D051858:Forkhead Transcription Factors; D017468:Receptors, Fibroblast Growth Factor; D014157:Transcription Factors; C090140:Whn protein; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; C496354:Fgfr2 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2