Combined deficiencies in Bruton tyrosine kinase and phospholipase Cgamma2 arrest B-cell development at a pre-BCR+ stage.
Bruton tyrosine kinase (Btk) and phospholipase Cgamma2 (PLCgamma2) are 2 key molecules involved in B-cell receptor (BCR) signaling. Biochemical studies have placed them in a linear signaling pathway, with Btk acting upstream of PLCgamma2. Consistent with this, mice lacking either molecule display a leaky but similar block in B-cell development. Here, we generated Btk(-/-) PLCgamma2(-/-) mice and showed that combined deficiencies in Btk and PLCgamma2 severely arrested B lymphopoiesis at the large pre-B-cell stage. In contrast to either single mutant, Btk(-/-) PLCgamma2(-/-) pre-B cells expressed high levels of pre-BCR on their cell surfaces and exhibited reduced immunoglobulin light chain gene rearrangements. Pre-BCR-induced calcium signaling was also drastically compromised in Btk(-/-) PLCgamma2(-/-) pre-B cells compared with wild-type and single-mutant cells. Interestingly, immunoglobulin heavy chain allelic exclusion remained intact in the absence of Btk and PLCgamma2. Overall, our results suggest that Btk and PLCgamma2 have combinatorial roles in regulating pre-B cell differentiation.
Xu
Shengli
S
Laboratory of Molecular and Cellular Immunology, Biomedical Sciences Institute, Agency for Science, Technology and Research, 61 Biopolis Drive, Singapore 138673. shengli@imcb.a-star.edu.sg
Lee
Koon-Guan
KG
Huo
Jianxin
J
Kurosaki
Tomohiro
T
Lam
Kong-Peng
KP
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D051966:Phospholipase C gamma / Q000172:deficiency* / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology
D007147:Immunoglobulin Light Chains; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D051966:Phospholipase C gamma