Btk and phospholipaseC gamma 2 can function independently during B cell development

The pre-BCR and the BCR regulate B cell development via a signalosome nucleated by the adaptor protein B cell linker protein (BLNK). Formation of this complex facilitates activation of phospholipaseC (PLC)2 by Bruton's tyrosine kinase (Btk). To determine whether Btk and PLC2 also have separate functions, we generated Btk-/-PLC2-/- mice. They demonstrated a block in development at the pre-Bstage and increased pre-BCR surface expression. This phenotype was more severe than that of Btk-/- or PLC2-/- mice. Although both Btk and PLC2 were required for proliferation of splenic B cells in response to BCR cross-linking, they contributed differently to anti-IgM-induced phosphorylation of ERK. Btk-/- and PLC2-/- mice each had a reduced frequency of Ig-expressing B cells and impaired migration of pre-B cells towards stromal cell-derived factor1. However, the increase in pre-B cell malignancy that occurs in BLNK-/- mice in the absence of Btk was not observed in the absence of PLC2. Thus, Btk and PLC2 act both in concert and independently throughout B cell development.