Loss of adenomatous polyposis coli gene function disrupts thymic development.
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 thymocytes 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.
Gounari
Fotini
F
Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111, USA. fgounari@tufts-nemc.org
Chang
Rui
R
Cowan
Janet
J
Guo
Zhuyan
Z
Dose
Marei
M
Gounaris
Elias
E
Khazaie
Khashayarsha
K
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000483:Alleles; D000705:Anaphase; D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D002871:Chromosome Banding; D048749:Cytokinesis; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D015321:Gene Rearrangement; D017491:Genes, APC; D005838:Genotype; D008565:Membrane Proteins / Q000378:metabolism; D008677:Metaphase; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis; D008957:Models, Genetic; D016133:Polymerase Chain Reaction; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D051880:Receptors, Notch; D011995:Recombination, Genetic; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology* / Q000254:growth & development*; D015534:Trans-Activators / Q000378:metabolism; D045567:VDJ Recombinases / Q000378:metabolism; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051880:Receptors, Notch; D015534:Trans-Activators; D051176:beta Catenin; D045567:VDJ Recombinases