Expression of JAGGED1 in T-lymphocytes results in thymic involution by inducing apoptosis of thymic stromal epithelial cells.
Proper development of the thymus and differentiation of T-lymphocytes requires cell-cell interactions between the developing T-lymphocytes and the thymic epithelia. The Delta/Serrate/Lag-2 (DSL)/Notch signal-transduction pathway is known to govern cell fate decisions required for proper development through direct cell-cell interactions. The functional consequences of specific DSL/Notch interactions during the development of a complex organ, such as the thymus, have not been thoroughly elucidated, however. In order to examine the role of DSL proteins during thymus development and T-lymphocyte differentiation, we targeted expression of JAGGED1 in T-lymphocyte progenitors via the control of the proximal lck promoter. Here, we report that expression of JAGGED1 in T cells causes premature involution of the thymus by directing thymic epithelial cells to undergo an apoptotic program. Adoptive transfer of JAGGED1 transgenic bone marrow into non-transgenic mice revealed that JAGGED1 expression on T cells does not alter T-cell differentiation, but is directly responsible for involution of the thymus. We propose that the phenotype of the lck-JAGGED1 transgenic mice is a direct result of specific DSL/Notch interactions and improper cell-to-cell signaling.
Beverly
L J
LJ
The Wistar Institute, Philadelphia, PA 19104, USA.
Ascano
J M
JM
Capobianco
A J
AJ
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C402726:Sh2d2a protein, mouse