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

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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.