PERINATAL LETHALITY AND BLOCKED B-CELL DEVELOPMENT IN MICE LACKING THE TYROSINE KINASE SYK

The tyrosine kinase Syk (relative molecular mass 72,000), which is wid ely expressed in haematopoietic cells, becomes associated with and act ivated by engagement of the B-cell antigen receptor(1,2). Furthermore, it has been implicated in signalling through the receptors for interl eukin-2 (IL-2)(3), granulocyte colony-stimulating factor (G-CSF)(4) an d Fc(5), the T cell receptor, as well as through receptors for several platelet agonists(7). A homologous kinase, ZAP-70, is crucial in sign alling through the T-cell receptor and in T-cell development(8,9). Usi ng homologous recombination in embryonic stem cells, we created mice n ull for the syk gene which showed petechiae in utero and died shortly after birth. Irradiated mice reconstituted with Syk-deficient fetal li ver showed a block in B-cell development at the pro-B to pre-B cell tr ansition, consistent with a key role for Syk in pre-B-cell receptor si gnalling. 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 mai ntenance of mature B cells. In addition, whereas the development of al pha beta T cells proceeded normally, Syk-deficient mice showed impaire d development of thymocytes using the V gamma 3 variable region gene ( V gamma 3(+) thymocytes). Finally, we show that Syk is not required fo r signalling through the IL-2 and G-CSF receptors.