Nature Immunology
6, 800 - 809 (2005)
Published online: 17 July 2005; | doi:10.1038/ni1228
Loss of adenomatous polyposis coli gene function disrupts thymic developmentFotini Gounari1, Rui Chang1, Janet Cowan2, Zhuyan Guo1, Marei Dose1, Elias Gounaris3, 4
& Khashayarsha Khazaie3, 41
Molecular Oncology Research Institute, Tufts−New England Medical Center, Boston, Massachusetts 02111, USA. 2
Department of Pediatrics, Tufts−New England Medical Center, Boston, Massachusetts 02111, USA. 3
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. 4
Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Correspondence should be addressed to Fotini Gounari fgounari@tufts-nemc.org or Khashayarsha Khazaie khashayarsha_khazaie@dfci.harvard.edu 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  -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) , encouraging developmental progression of aberrant thymocytes lacking pre-TCR and  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 -catenin signaling and is essential for T cell differentiation.
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