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 receptor. Transient overexpression of SLP-76 in a T-cell line potentiates transcriptional activation after T-cell receptor ligation, while loss of SLP-76 expression abrogates several T-cell receptor-dependent signaling pathways. Mutant mice that lack SLP-76 manifest a severe block at an early stage of thymocyte development, implicating SLP-76 in signaling events that promote thymocyte maturation. While it is clear that SLP-76 plays a key role in development and activation of T lymphocytes, relatively little is understood regarding its role in transducing signals initiated after receptor ligation in other hematopoietic cell types. In this report, we describe fetal hemorrhage and perinatal mortality in SLP-76-deficient mice. Although megakaryocyte and platelet development proceeds normally in the absence of SLP-76, collagen-induced platelet aggregation and granule release is markedly impaired. Furthermore, treatment of SLP-76-deficient platelets with collagen fails to elicit tyrosine phosphorylation of phospholipase C-gamma2 (PLC-gamma2), suggesting that SLP-76 functions upstream of PLC-gamma2 activation. These data provide one potential mechanism for the fetal hemorrhage observed in SLP-76-deficient mice and reveal that SLP-76 expression is required for optimal receptor-mediated signal transduction in platelets as well as T lymphocytes.
Clements
J L
JL
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Lee
J R
JR
Gross
B
B
Yang
B
B
Olson
J D
JD
Sandra
A
A
Watson
S P
SP
Lentz
S R
SR
Koretzky
G A
GA
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology; D003094:Collagen / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism; D005333:Fetus / Q000002:abnormalities*; D006470:Hemorrhage / Q000473:pathology*; D006651:Histocytochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000172:deficiency*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis; D010974:Platelet Aggregation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D010750:Phosphoproteins; D011956:Receptors, Cell Surface; C092947:SLP-76 signal Transducing adaptor proteins; D019000:Phosphotyrosine; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D010738:Type C Phospholipases; D051966:Phospholipase C gamma