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.
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