Phospholipase Cγ2 Mediates RANKL-stimulated Lymph Node Organogenesis and Osteoclastogenesis

Phospholipase C gamma 2 (PLC gamma 2) is an important signaling effector of multiple receptors in the immune system. Here we show that PLC gamma 2-deficient mice displayed impaired lymph node organogenesis but normal splenic structure and Peyer's patches. Receptor activator of NF-kappa Bligand (RANKL) is a tumor necrosis factor family cytokine and is essential for lymph node organogenesis. Importantly, PLC gamma 2 deficiency severely impaired RANKL signaling, resulting in marked reduction of RANKL-induced activation of MAPKs, p38 and JNK, but not ERK. The lack of PLC gamma 2 markedly diminished RANKL-induced activation of NF-kappa B, AP-1, and NFATc1. Moreover, PLC gamma 2 deficiency impaired RANKL-mediated biological function, leading to failure of the PLC gamma 2- deficient bone marrow macrophage precursors to differentiate into osteoclasts after RANKL stimulation. Re-introduction of PLC gamma 2 but not PLC gamma 1 restores RANKL-mediated osteoclast differentiation of PLC gamma 2- deficient bone marrow-derived monocyte/macrophage. Taken together, PLC gamma 2 is essential for RANK signaling, and its deficiency leads to defective lymph node organogenesis and osteoclast differentiation.