Direct BMP2/4 signaling through BMP receptor IA regulates fetal thymocyte progenitor homeostasis and differentiation to CD4+CD8+ double-positive cell.
BMP2/4 signaling is required for embryogenesis and involved in thymus morphogenesis and T-lineage differentiation. In vitro experiments have shown that treatment of thymus explants with exogenous BMP4 negatively regulated differentiation of early thymocyte progenitors and the transition from CD4-CD8- (DN) to CD4+CD8+ (DP). Here we show that in vivo BMP2/4 signaling is required for fetal thymocyte progenitor homeostasis and expansion, but negatively regulates differentiation from DN to DP cell. Unexpectedly, conditional deletion of BMPRIA from fetal thymocytes (using the Cre-loxP system and directing excision to hematopoietic lineage cells with the Vav promoter) demonstrated that physiological levels of BMP2/4 signaling directly to thymocytes through BMPRIA are required for normal differentiation and expansion of early fetal DN thymocytes. In contrast, the arrest in early thymocyte progenitor differentiation caused by exogenous BMP4 treatment of thymus explants is induced in part by direct signaling to thymocytes through BMPRIA, and in part by indirect signaling through non-hematopoietic cells. Analysis of the transition from fetal DN to DP cell, both by ex vivo analysis of conditional BMPRIA-deficient thymocytes and by treatment of thymus explants with the BMP4-inhibitor Noggin demonstrated that BMP2/4 signaling is a negative regulator at this stage. We showed that at this stage of fetal T-cell development BMP2/4 signals directly to thymocytes through BMPRIA.
Department of Animal Science and Aquaculture; Laboratory of Animal Breeding and Husbandry; Agricultural University of Athens; Athens, Greece.
Ariadne L
AL
Hager-Theodorides
Immunobiology Unit; UCL Institute of Child Health; London, UK.
Susan E
SE
Ross
Immunobiology Unit; UCL Institute of Child Health; London, UK.
Hemant
H
Sahni
University of Michigan; School of Dentistry; Department of Biologic and Materials Sciences; Ann Arbor, MI USA.
Yuji
Y
Mishina
Immunobiology Unit; UCL Institute of Child Health; London, UK.
Anna L
AL
Furmanski
Immunobiology Unit; UCL Institute of Child Health; London, UK.
Tessa
T
Crompton
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D015704:CD4 Antigens / Q000378:metabolism*; D016827:CD8 Antigens / Q000378:metabolism*; D002454:Cell Differentiation; D005333:Fetus / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology / Q000254:growth & development
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D015704:CD4 Antigens; D016827:CD8 Antigens; D052005:Bone Morphogenetic Protein Receptors, Type I
Alk3; BMP2/4; BMPRIA; DN thymocyte; DP; Noggin; Smad; T-cell development; differentiation; thymus