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Phospholipase C2 Dosage Is Critical for B Cell Development in the Absence of Adaptor Protein BLNK¹

Shengli Xu^*, Jianxin Huo^*, Weng-Keong Chew^*, Masaki Hikida, Tomohiro Kurosaki and Kong-Peng Lam^2,*

^* Laboratory of Immunology, Center for Molecular Medicine and Institute of Molecular and Cell Biology, Singapore; and Laboratory of Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

B cell linker (BLNK) protein and phospholipase C2 (PLC2) are components of the BCR signalosome that activate calcium signaling in B cells. Mice lacking either molecule have a severe but incomplete block in B lymphopoiesis. In this study, we generated BLNK^–/–PLC2^–/– mice to examine the effect of simultaneous disruption of both molecules on B cell development. We showed that BLNK^–/–PLC2^–/– mice had compounded defects in B cell maturation compared with either single mutant, suggesting that these two molecules cooperatively or synergistically signaled B lymphopoiesis. However, Ig H chain allelic exclusion was maintained in single and double mutants, indicating that signals propagated by BLNK and PLC2 were not involved in this process. Interestingly, in the absence of BLNK, B cell development was dependent on plc2 gene dosage. This was evidenced by the proportionate decrease in splenic B cell population and increase in bone marrow surface pre-BCR⁺ cells in PLC2-diploid, -haploid, and -null animals. Intracellular calcium signaling and ERK activation in response to BCR engagement were also proportionately decreased and delayed, respectively, with stepwise reduction of plc2 dosage in a BLNK^null background. Thus, these data indicate the importance of BLNK not only as a conduit to specifically channel BCR-signaling pathways and as a scaffold for the assembling of macromolecular complex, but also as an efficient aggregator or concentrator of PLC2 molecules to effect optimal signaling for B cell generation and activation.

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