Showing papers by "Martin R Turner published in 1995"

Perinatal lethality and blocked b-cell development in mice lacking the tyrosine kinase syk

Abstract: The tyrosine kinase Syk (relative molecular mass 72,000), which is widely expressed in haematopoietic cells, becomes associated with and activated by engagement of the B-cell antigen receptor. Furthermore, it has been implicated in signalling through the receptors for interleukin-2 (IL-2), granulocyte colony-stimulating factor (G-CSF) and Fc, the T cell receptor, as well as through receptors for several platelet agonists. A homologous kinase, ZAP-70, is crucial in signalling through the T-cell receptor and in T-cell development. Using homologous recombination in embryonic stem cells, we created mice null for the syk gene which showed petechiae in utero and died shortly after birth. Irradiated mice reconstituted with Syk-deficient fetal liver showed a block in B-cell development at the pro-B to pre-B cell transition, consistent with a key role for Syk in pre-B-cell receptor signalling. Despite the production of small numbers of immature B cells, Syk-deficient radiation chimaeras failed to accumulate mature B cells, indicating a possible role for this protein in the production or maintenance of mature B cells. In addition, whereas the development of alpha beta T cells proceeded normally, Syk-deficient mice showed impaired development of thymocytes using the V gamma 3 variable region gene (V gamma 3+ thymocytes). Finally, we show that Syk is not required for signalling through the IL-2 and G-CSF receptors.

Defective antigen receptor-mediated proliferation of B and T cells in the absence of Vav

Abstract: CROSSLINKING of B- or T-cell antigen receptors results in the rapid tyrosine phosphorylation of a number of proteins, including Vav, a protein expressed in cells of the haematopoietic system1–3. Vav contains an array of structural motifs that include Src-homology domains SH2/SH34 and regions of homology to the guanine-nucleotide-exchange protein Dbl, pleckstrin and protein kinase C (refs 5-9). Using the RAG-complementation approach10, we have analysed in vivo differentiation and in vitro responses of B-and T-lineage cells generated by injection of embryonic stem cells homozygous for a null mutation in the vav gene into blastocysts of RAG-1- or RAG-2-deficient mice. Here we report that antigen receptor-mediated proliferative responses of B and T cells in vitro are severely reduced in the absence of Vav. We also suggest a direct link between the low proliferative response of Vav-deficient B and T cells and the reduced number of these cells in peripheral lymphoid organs of chimaeric mice.

Nucleic acid encoding modified human tnfα (tumor necrosis factor alpha) receptor

Abstract: A DNA molecule is provided which encodes a polypeptide which is capable of binding human TNFα and which has the first three cysteine-rich subdomains, but not the fourth cysteine-rich subdomain, of the extracellular binding domain of a receptor selected from the 55 kD and 75 kD receptors for human TNFα. The ability of the polypeptide to bind to TNFα means that it can be used for treating diseases mediated by TNFα activity, such as rheumatoid arthritis.