Activation of Wnt/?-catenin protein signaling induces mitochondria-mediated apoptosis in hematopoietic progenitor cells.

ABSTRACT: The canonical Wnt/?-catenin signaling is activated during development, tumorigenesis, and in adult homeostasis, yet its role in maintenance of hematopoietic stem/progenitor cells is not firmly established. Here, we demonstrate that conditional expression of an active form of ?-catenin in vivo induces a marked increase in the frequency of apoptosis in hematopoietic stem/progenitor cells (HSCs/HPCs). Activation of Wnt/?-catenin signaling in HPCs in vitro elevates the activity of caspases 3 and 9 and leads to a loss of mitochondrial membrane potential (??(m)), indicating that it induces the intrinsic mitochondrial apoptotic pathway. In vivo, expression of activated ?-catenin in HPCs is associated with down-regulation of Bcl2 and expression of Casp3. Bone marrow transplantation assays reveal that enhanced cell survival by a Bcl2 transgene re-establishes the reconstitution capacity of HSCs/HPCs that express activated ?-catenin. In addition, a Bcl2 transgene prevents exhaustion of these HSCs/HPCs in vivo. Our data suggest that activation of the Wnt/?-catenin pathway contributes to the defective function of HPCs in part by deregulating their survival.

SUBMITTER: Ming M 

PROVIDER: S-EPMC3391123 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature