Mutation of tyrosine 145 of lymphocyte cytosolic protein 2 protects mice from anaphylaxis and arthritis.

Background: Lymphocyte cytosolic protein 2, also known as Src homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76), is an essential adaptor molecule in myeloid cells, where it regulates FcepsilonRI-induced mast cell (MC) and FcgammaR- and integrin-induced neutrophil (polymorphonuclear leukocyte [PMN]) functions. SLP-76 contains 3 N-terminal tyrosines at residues 112, 128, and 145 that together are critical for its function.

Objective: We sought to explore the relative importance of tyrosines 112, 128, and 145 of SLP-76 during MC and PMN activation.

Cutting edge: rescue of pre-TCR but not mature TCR signaling in mice expressing membrane-targeted SLP-76.

SLP-76 (Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa) organizes signaling from immunoreceptors, including the platelet collagen receptor, the pre-TCR, and the TCR, and is required for T cell development. In this study we examine a mouse in which wild-type SLP-76 is replaced with a mutant constitutively targeted to the cell membrane. Membrane-targeted SLP-76 (MTS) supports ITAM signaling in platelets and from the pre-TCR.

Extramedullary erythropoiesis in the adult liver requires BMP-4/Smad5-dependent signaling.

Objective: In mice, homeostatic erythropoiesis occurs primarily in the bone marrow. However, in response to acute anemia, bone morphogenetic proteins 4 (BMP-4)-dependent stress erythropoiesis occurs in the adult spleen. BMP-4 can also regulate stress erythropoiesis in the fetal liver.

An intronic sequence mutated in flexed-tail mice regulates splicing of Smad5.

Recent work has identified a growing body of evidence that subtle changes in noncoding sequences can result in significant pathology. These mutations, which would have been called silent polymorphisms in the past, affect gene transcription and mRNA splicing and lead to drastic changes in gene expression. Previous work from our lab has characterized the murine flexed-tail (f) mutation, which encodes Smad5, a transcription factor that functions downstream of the receptors for bone morphogenetic proteins (BMPs).

Loss of SLP-76 expression within myeloid cells confers resistance to neutrophil-mediated tissue damage while maintaining effective bacterial killing.

The Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) is an adaptor molecule critical for immunoreceptor and integrin signaling in multiple hemopoietic lineages. We showed previously that SLP-76 is required for neutrophil function in vitro, including integrin-induced adhesion and production of reactive oxygen intermediates, and to a lesser extent, FcgammaR-induced calcium flux and reactive oxygen intermediate production. It has been difficult to determine whether SLP-76 regulates neutrophil responses in vivo, because Slp-76(-/-) mice exhibit marked defects in thymocyte and vascular development, as well as platelet and mast cell function.

BMP4 and Madh5 regulate the erythroid response to acute anemia.

Acute anemia initiates a systemic response that results in the rapid mobilization and differentiation of erythroid progenitors in the adult spleen. The flexed-tail (f) mutant mice exhibit normal steady-state erythropoiesis but are unable to rapidly respond to acute erythropoietic stress. Here, we show that f/f mutant mice have a mutation in Madh5.