Abstract
Despite the absence of the genome in platelets, transcription profiling provides important insights into platelet function and can help clarify abnormalities in platelet disorders. The Bloodomics Consortium performed whole-genome expression analysis comparing in vitro–differentiated megakaryocytes (MKs) with in vitro–differentiated erythroblasts and different blood cell types. This allowed the identification of genes with upregulated expression in MKs compared with all other cell lineages, among the receptors BAMBI, LRRC32, ESAM, and DCBLD2. In a later correlative analysis of genome-wide platelet RNA expression with interindividual human platelet reactivity, LLRFIP and COMMD7 were additionally identified. A functional genomics approach using morpholino-based silencing in zebrafish identified various roles for all of these selected genes in thrombus formation. In this review, we summarize the role of the six identified genes in zebrafish and discuss how they correlate with subsequently performed mouse experiments.
Highlights
Despite the absence of the genome in platelets, transcription profiling provides important insights into platelet function and can help clarify abnormalities in platelet disorders
Other studies showed that inhibition of the expression of myosin light chain kinase 1a and protein kinase Cα and β resulted in an attenuated thrombus formation compared with controls.[36,37]. These results demonstrated that the effects of proteins with a known relevance in human platelet function could be reproduced in experiments using the laser-induced thrombosis model in zebrafish, once more indicating that the model seems well applicable for the investigation of the function of the newly identified genes
The exact mode of action of LRR-binding FLII interacting protein 1 (LRRFIP1) remains unclear, as LRRFIP1 interacts with Flightless 1 (FLI1) and Debrin 1 (DBN1), both involved in the modulation of the cytoskeleton, it is possible that LRRFIP1 may contribute to cytoskeletal regulation of platelet activation.[19]
Summary
Blood platelets are important mediators of thrombus formation. addressing the platelet genome is challenging, as platelets are anucleated cells derived from megakaryocytes (MKs) in the bone marrow. As many known MK/platelet-specific membrane proteins are expressed in endothelial cells, the genes expressed in both MK and resting human umbilical vein endothelial cells (HUVECs) were identified, narrowing down the number genes to 35 Of these 35 genes, 4 genes were selected for further analysis due to their unknown role in hemostasis and thrombosis, interesting protein domains, and human and zebrafish orthology.[3,4] Expression of all four proteins was confirmed in human platelets.[4]. To clarify the putative role of all these genes in thrombosis and hemostasis, functional genomic studies were needed, using the zebrafish model as a first rapid screening method
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