Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice

The adapter protein SLP-76 is expressed in T lymphocytes and hematopoietic cells of the myeloid lineage, and is known to be a substrate of the protein tyrosine kinases that are activated after ligation of the T-cell antigen r eceptor. Transient overexpression of SLP-76 in a T-cell line potentiates tr anscriptional activation after T-cell receptor ligation, while loss of SLP- 76 expression abrogates several T-cell receptor-dependent signaling pathway s. Mutant mice that lack SLP-76 manifest a severe block at an early stage o f thymocyte development, implicating SLP-76 in signaling events that promot e thymocyte maturation. While it is clear that SLP-76 plays a key role in d evelopment and activation of T lymphocytes, relatively little is understood regarding its role in transducing signals initiated after receptor ligatio n in other hematopoietic cell types. In this report, we describe fetal hemo rrhage and perinatal mortality in SLP-76-deficient mice. Although megakaryo cyte and platelet development proceeds normally in the absence of SLP-76, c ollagen-induced platelet aggregation and granule release is markedly impair ed Furthermore, treatment of SLP-76-deficient platelets with collagen fails to elicit tyrosine phosphorylation of phospholipase C-gamma 2 (PLC-gamma 2 ), suggesting that SLP-76 functions upstream of PLC-gamma 2 activation. The se data provide one potential mechanism for the fetal hemorrhage observed i n SLP-76-deficient mice and reveal that SLP-76 expression is required for o ptimal receptor-mediated signal transduction in platelets as well as T lymp hocytes.