Impact of conditional deletion of the pro-apoptotic BCL-2 family member BIM in mice.

M J Herold,D Mérino,R Stuchbery,D Hildeman,A Strasser,T Willson,P Bouillet

doi:10.1038/cddis.2014.409

Abstract

The pro-apoptotic BH3-only BCL-2 family member BIM is a critical determinant of hematopoietic cell development and homeostasis. It has been argued that the striking hematopoietic abnormalities of BIM-deficient mice (accumulation of lymphocytes and granulocytes) may be the result of the loss of the protein throughout the whole animal rather than a consequence intrinsic to the loss of BIM in hematopoietic cells. To address this issue and allow the deletion of BIM in specific cell types in future studies, we have developed a mouse strain with a conditional Bim allele as well as a new Cre transgenic strain, Vav-CreER, in which the tamoxifen-inducible CreER recombinase (fusion protein) is predominantly expressed in the hematopoietic system. We show that acute loss of BIM in the adult mouse rapidly results in the hematopoietic phenotypes previously observed in mice lacking BIM in all tissues. This includes changes in thymocyte subpopulations, increased white blood cell counts and resistance of lymphocytes to BIM-dependent apoptotic stimuli, such as cytokine deprivation. We have validated this novel conditional Bim knockout mouse model using established and newly developed CreER strains (Rosa26-CreER and Vav-CreER) and will make these exciting new tools for studies on cell death and cancer available.

Highlights

BIM is a critical initiator of the mitochondrial apoptotic pathway, in hematopoietic cells.[5]
These results demonstrate that (i) the loxP sequences do not alter the expression of the BIM protein or its function and (ii) that deletion of the floxed Bim allele recapitulates the phenotype observed in the constitutive Bim knockout mice
We report here the development of a new floxed Bim allele, which allows the deletion of this pro-apoptotic BH3-only protein in a cell type-restricted and temporally controllable manner

Summary

Introduction

BIM is a critical initiator of the mitochondrial apoptotic pathway, in hematopoietic cells.[5]. T-cell apoptosis during the shutdown of an immune response.[8,9] BIM is a tumor suppressor in mantle cell lymphoma, where the gene is lost,[10] as well as Burkitt’s lymphoma and renal carcinoma in which the gene is silenced.[11,12] Loss of BIM renders cells resistant to several pro-apoptotic stimuli, such as withdrawal of growth factors, treatment with calcium ionophores[5] or ER stress.[13] This information about BIM’s physiological function was derived from the study of a mouse strain in which the Bim gene was constitutively inactivated in all cell types.[5] The complete absence of a gene product during the entire life of an animal can lead to phenotypes that are not cell-autonomous and may lead to compensatory events (for example, upregulation of genes with overlapping function). We developed a conditional Bim allele allowing for temporally and spatially controllable deletion of this critical

Methods

Results

Conclusion