Abstract
The molecular mechanisms regulating lymphocyte lineage commitment remain poorly characterized. To explore the role of the IL7R in this process, we generated transgenic mice that express a constitutively active form of STAT5 (STAT5b-CA), a key downstream IL7R effector, throughout lymphocyte development. STAT5b-CA mice exhibit a 40-fold increase in pro-B cells in the thymus. As documented by BrdU labeling studies, this increase is not due to enhanced B cell proliferation. Thymic pro-B cells in STAT5b-CA mice show a modest increase in cell survival ( approximately 4-fold), which correlates with bcl-x(L) expression. However, bcl-x(L) transgenic mice do not show increases in thymic B cell numbers. Thus, STAT5-dependent bcl-x(L) up-regulation and enhanced B cell survival are not sufficient to drive the thymic B cell development observed in STAT5b-CA mice. Importantly, thymic pro-B cells in STAT5b-CA mice are derived from early T cell progenitors (ETPs), suggesting that STAT5 acts by altering ETP lineage commitment. Supporting this hypothesis, STAT5 binds to the pax5 promoter in ETPs from STAT5b-CA mice and induces pax5, a master regulator of B cell development. Conversely, STAT5b-CA mice exhibit a decrease in the DN1b subset of ETPs, demonstrating that STAT5 activation inhibits early T cell differentiation or lineage commitment. On the basis of these findings, we propose that the observed expression of the IL-7R on common lymphoid progenitors, but not ETPs, results in differential STAT5 signaling within these distinct progenitor populations and thus helps ensure appropriate development of B cells and T cells in the bone marrow and thymic environments, respectively.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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B-Lymphocyte Subsets / cytology*
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B-Lymphocyte Subsets / immunology*
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B-Lymphocyte Subsets / metabolism
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Cell Lineage / genetics
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Cell Lineage / immunology
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Cell Proliferation
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Cell Survival / genetics
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Cell Survival / immunology
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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DNA-Binding Proteins / physiology
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Growth Inhibitors / genetics
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Growth Inhibitors / metabolism
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Growth Inhibitors / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Milk Proteins / genetics
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Milk Proteins / metabolism*
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PAX5 Transcription Factor
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Promoter Regions, Genetic
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Protein Binding / genetics
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Protein Binding / immunology
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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STAT5 Transcription Factor
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Signal Transduction / genetics
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Signal Transduction / immunology
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Stem Cells / cytology
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Stem Cells / immunology
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Stem Cells / metabolism
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T-Lymphocyte Subsets / cytology*
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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Thymus Gland / cytology*
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Thymus Gland / immunology*
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Thymus Gland / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Trans-Activators / physiology
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Up-Regulation / genetics
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Up-Regulation / immunology
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bcl-X Protein
Substances
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Bcl2l1 protein, mouse
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DNA-Binding Proteins
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Growth Inhibitors
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Milk Proteins
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PAX5 Transcription Factor
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Pax5 protein, mouse
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Proto-Oncogene Proteins c-bcl-2
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STAT5 Transcription Factor
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Stat5b protein, mouse
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Trans-Activators
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Transcription Factors
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bcl-X Protein