Early death and severe lymphopenia caused by ubiquitous expression of the Rag1 and Rag2 genes in mice

Abstract

The recombination activating proteins (RAG1 and RAG2) are essential for V(D)J recombination of immunoglobulin chains. Expression of both genes is lymphocyte-specific and RAG levels are tightly regulated throughout lymphopoiesis and cell cycle. To assess the significance of this pattern of expression, we generated transgenic mice expressing the Rag genes both continuously throughout lymphocyte development and constitutively in most non-lymphoid tissues. The transgenes partially complement an endogenous Rag2 null mutation and lead to a partial block in early B and T lymphopoiesis when introduced on a Rag2 sufficient background. The defect in thymocyte number is restricted to the alpha beta lineage leaving the gamma delta T cell pool intact, while neither IgH phenotypic allelic exclusion nor the kappa/lambda light chain ratio are altered. Finally, the ectopic expression of the Rag genes associates with growth retardation and early death of the animals, a phenotype reminiscent of those reported for mice deficient in double-strand break repair molecules.