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PMID:20525922

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Citation

Halene, S, Gao, Y, Hahn, K, Massaro, S, Italiano, JE Jr, Schulz, V, Lin, S, Kupfer, GM and Krause, DS (2010) Serum response factor is an essential transcription factor in megakaryocytic maturation. Blood 116:1942-50

Abstract

Serum response factor (Srf) is a MADS-box transcription factor that is critical for muscle differentiation. Its function in hematopoiesis has not yet been revealed. Mkl1, a cofactor of Srf, is part of the t(1;22) translocation in acute megakaryoblastic leukemia, and plays a critical role in megakaryopoiesis. To test the role of Srf in megakaryocyte development, we crossed Pf4-Cre mice, which express Cre recombinase in cells committed to the megakaryocytic lineage, to Srf(F/F) mice in which functional Srf is no longer expressed after Cre-mediated excision. Pf4-Cre/Srf(F/F) knockout (KO) mice are born with normal Mendelian frequency, but have significant macrothrombocytopenia with approximately 50% reduction in platelet count. In contrast, the BM has increased number and percentage of CD41(+) megakaryocytes (WT: 0.41% ± 0.06%; KO: 1.92% ± 0.12%) with significantly reduced ploidy. KO mice show significantly increased megakaryocyte progenitors in the BM by FACS analysis and CFU-Mk. Megakaryocytes lacking Srf have abnormal stress fiber and demarcation membrane formation, and platelets lacking Srf have abnormal actin distribution. In vitro and in vivo assays reveal platelet function defects in KO mice. Critical actin cytoskeletal genes are down-regulated in KO megakaryocytes. Thus, Srf is required for normal megakaryocyte maturation and platelet production partly because of regulation of cytoskeletal genes.

Links

PubMed PMC3173990 Online version:10.1182/blood-2010-01-261743

Keywords

Animals; Bleeding Time; Blood Platelets/cytology; Blood Platelets/metabolism; Bone Marrow Cells/cytology; Bone Marrow Cells/metabolism; Cell Differentiation; Cell Lineage; Cells, Cultured; Cytoskeleton/metabolism; Cytoskeleton/ultrastructure; Female; Flow Cytometry; Gene Expression Profiling; Luminescent Proteins/genetics; Luminescent Proteins/metabolism; Male; Megakaryocytes/cytology; Megakaryocytes/metabolism; Megakaryocytes/ultrastructure; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Electron, Transmission; Platelet Count; Platelet Factor 4/genetics; Platelet Factor 4/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Serum Response Factor/genetics; Serum Response Factor/metabolism; Thrombocytopenia/genetics; Thrombocytopenia/metabolism; Thrombocytopenia/pathology; Transcription Factors/genetics; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SRF

acts_upstream_of_or_within

GO:0030220: platelet formation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3522206,MGI:MGI:3764698

P

Seeded From UniProt

complete

MOUSE:SRF

acts_upstream_of_or_within

GO:0030168: platelet activation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3522206,MGI:MGI:3764698

P

Seeded From UniProt

complete

MOUSE:SRF

acts_upstream_of_or_within

GO:0007160: cell-matrix adhesion

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3522206,MGI:MGI:3764698

P

Seeded From UniProt

complete

MOUSE:SRF

acts_upstream_of_or_within

GO:0043149: stress fiber assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3522206,MGI:MGI:3764698

P

  • occurs_in:(CL:0000556)|occurs_in:(CL:0000233)

Seeded From UniProt

complete

MOUSE:SRF

acts_upstream_of_or_within

GO:0035855: megakaryocyte development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3522206,MGI:MGI:3764698

P

  • occurs_in:(EMAPA:32760)|occurs_in:(EMAPA:18767)

Seeded From UniProt

complete


See also

References

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