The Adaptor Protein Shc Plays a Key Role in Early B Cell Development (138.22)

Abstract

Abstract B cell development is a highly ordered process that requires immature cells to pass through multiple checkpoints to advance through development. Successful expression and productive signaling via antigen and cytokine receptors are required at specific stages of development. The adaptor protein Shc is phosphorylated on three critical tyrosine residues and facilitates signaling downstream of multiple receptors, including the pre-T cell receptor. However, its role in B cell development is currently unknown. Here, using a Cre-loxP mediated approach, we inducibly expressed as transgenes either wild type Shc or a mutant form Shc (ShcFFF, where three critical tyrosines have been mutated). Igα-Cre-mediated induction of ShcFFF expression (but not wt Shc) at the common lymphoid progenitor stage resulted in a severe block at the pre-pro-B to pro-B transition, with diminished numbers maintained throughout B development. Expression of ShcFFF at later stages of B cell development (via CD19-Cre) showed no defect in B cell numbers, emphasizing the importance of Shc during early B development. Mechanistically, Shc appears to affect B cell development at the level of cytokine dependent proliferation, as well as pre-BCR signaling. These results suggest a non-redundant role for Shc in early B development.