Loss of adenomatous polyposis coli gene function disrupts thymic development.
Journal:
Nat. Immunol. 2005 AugAuthors:
Gounari F, Chang R, Cowan J, Guo Z, Dose M, Gounaris E, Khazaie K
Abstract
Loss of the adenomatous polyposis coli (APC) protein is a common initiating event in colon cancer. Here we show that thymocyte-specific loss of APC deregulated beta-catenin signaling and suppressed Notch-dependent transcription. These events promoted the proliferation of cells of the double-negative 3 and 4 stages and reduced rearrangements between the variable, diversity and joining regions of the gene encoding T cell receptor (TCR) beta, encouraging developmental progression of aberrant thymoc
...[more]ytes lacking pre-TCR and alphabeta TCR. Simultaneously, the loss of APC prolonged the mitotic metaphase-to-anaphase checkpoint and impaired chromosome segregation, blocking development beyond the double-negative 4 stage. The result was extensive thymic atrophy and increased frequencies of thymocytes with chromosomal abnormalities. Thus, loss of APC in immature thymocytes has consequences distinct from those of deregulation of beta-catenin signaling and is essential for T cell differentiation.[less]
Mesh Headings:
Adenomatous Polyposis Coli Protein, Alleles, Anaphase, Animals, Cell Proliferation, Cell Survival, Cells, Cultured, Chromosome Aberrations, Chromosome Banding, Cytokinesis, Cytoskeletal Proteins, Flow Cytometry, Gene Expression Regulation, Developmental, Gene Rearrangement, Genes, APC, Genotype, Membrane Proteins, Metaphase, Mice, Mice, Transgenic, Mitosis, Models, Genetic, Polymerase Chain Reaction, Receptors, Antigen, T-Cell, alpha-beta, Receptors, Notch, Recombination, Genetic, Retroviridae, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, T-Lymphocytes, Thymus Gland, Trans-Activators, VDJ Recombinases, beta Catenin