The variable, CH1, CH2 and CH3 domains of lg heavy chain are dispensable for pre-BCR function in transgenic mice

Abstract

The pre-BCR consists of Ig μ protein, the product of a heavy chain gene assembled by V(D)J recombination in pro-B cells, the surrogate light chains Vpre-B and λ5, and the signaling chains Igα and Igβ. Signaling by the pre-BCR is a checkpoint required for further maturation of pro-B cells in the adult bone marrow. However, it is currently not known whether an extracellular ligand is required to initiate pre-BCR signaling. We reasoned that if the ectodomain of the pre-BCR is required to interact with a ligand, then a truncated heavy chain protein would not support B cell development. To test this notion, we produced transgenic mice expressing a heavy chain protein whose extracellular domains except for CH4 were replaced by an irrelevant Ig superfamily ectodomain from the human CD8α protein. This transgene resulted in pre-BCR-like signaling since it rescued development of pre-B cells in recombinase-activating gene (RAG)1-deficient mice and resulted in allelic exclusion of the endogenous Ig heavy chain gene in RAG-proficient mice. These findings lead us to suggest that the majority of the extracellular region of the pre-BCR is not required for pre-BCR function and, thus, ligand binding is unlikely to be required for pre-BCR function.