What goes up must come down: The consequences of not turning down pre-TCR induced β-catenin (36.29)

Abstract

Abstract Pre-T cell receptor (pre-TCR) signals regulate β-selection during the maturation of CD4- CD8- double negative (DN) thymocytes to the CD4+ CD8+ double positive (DP) stage. T-cell specific deletion of β-catenin, a central mediator of Wnt- β-catenin-TCF/LEF signaling pathway, impairs T cell development at the β-selection checkpoint. We demonstrate that pre-TCR signals specifically stabilize β-catenin in DN thymocytes during β-selection. Pre-TCR induced β-catenin regulates expression of IL-7 receptor (IL-7R), early growth response (Egr) and Ror-γ-T genes that are essential for traversal through β-selection checkpoint. However, expression of pre-TCR induced β-catenin must be transient and must return to background levels for efficient transition to the DP stage. Sustained expression of β-catenin results in the development of IL-7R and Egr expressing pre-DP thymocytes that fail to up-regulate the expression of Ror-γ-T, which is essential for development to the DP stage. The stalled DN cells, expressing β-catenin, exhibit DNA damage, growth arrest, oncogene-induced-senescence (OIS) and p53 dependent apoptosis. In p53-deficient mice, expression of β-catenin still results in DNA damage and OIS, but the thymocytes survive and eventually progress to thymic lymphoma. We suggest that oncogenic β-catenin is a part of normal developmental signaling event but is prevented from transforming developing thymocytes by p53-independent growth arrest and OIS and p53-dependent apoptosis.