Molecular pathways and mechanisms regulating the recombination of immunoglobulin genes during B-lymphocyte development.

The hallmark of B-cell development is the ordered recombination of immunoglobulin (Ig) genes. Recently, considerable progress has been achieved in assembling gene regulatory networks comprised of signaling components and transcription factors that regulate B-cell development. In this chapter we synthesize experimental evidence to explain how such signaling pathways and transcription factors can orchestrate the ordered recombination of immunoglobulin (Ig) genes. Recombination of antigen-receptor loci is regulated both by the developmentally controlled expression of the Rag1 and Rag2 genes and the accessibility of particular loci and their gene segments to recombination. A new framework has emerged that invokes nuclear compartmentalization, large-scale chromatin dynamics and localized changes in chromatin structure in regulating the accessibility of Ig loci at specific stages of B-cell development. We review this emergent framework and discuss new experimental approaches that will be needed to explore the underlying molecular mechanisms.