Serum response factor is an essential transcription factor in megakaryocytic maturation
- PMID: 20525922
- PMCID: PMC3173990
- DOI: 10.1182/blood-2010-01-261743
Serum response factor is an essential transcription factor in megakaryocytic maturation
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.
Figures
![Figure 1](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3173990/bin/zh89991056840001.gif)
![Figure 2](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3173990/bin/zh89991056840002.gif)
![Figure 3](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3173990/bin/zh89991056840003.gif)
![Figure 4](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3173990/bin/zh89991056840004.gif)
![Figure 5](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3173990/bin/zh89991056840005.gif)
![Figure 6](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3173990/bin/zh89991056840006.gif)
![Figure 7](https://cdn.statically.io/img/www.ncbi.nlm.nih.gov/pmc/articles/instance/3173990/bin/zh89991056840007.gif)
Comment in
-
Megakaryocytes muscle in.Blood. 2010 Sep 16;116(11):1828-9. doi: 10.1182/blood-2010-06-291369. Blood. 2010. PMID: 20847210 No abstract available.
Similar articles
-
MKL1 and MKL2 play redundant and crucial roles in megakaryocyte maturation and platelet formation.Blood. 2012 Sep 13;120(11):2317-29. doi: 10.1182/blood-2012-04-420828. Epub 2012 Jul 17. Blood. 2012. PMID: 22806889 Free PMC article.
-
Role for MKL1 in megakaryocytic maturation.Blood. 2009 Mar 19;113(12):2826-34. doi: 10.1182/blood-2008-09-180596. Epub 2009 Jan 9. Blood. 2009. PMID: 19136660 Free PMC article.
-
Broader expression of the mouse platelet factor 4-cre transgene beyond the megakaryocyte lineage.J Thromb Haemost. 2015 Jan;13(1):115-25. doi: 10.1111/jth.12784. Epub 2014 Dec 17. J Thromb Haemost. 2015. PMID: 25393502
-
Megakaryocyte modification of platelets in thrombocytopenia.Curr Opin Hematol. 2018 Sep;25(5):410-415. doi: 10.1097/MOH.0000000000000451. Curr Opin Hematol. 2018. PMID: 29985173 Review.
-
Megakaryopoiesis and Platelet Biology: Roles of Transcription Factors and Emerging Clinical Implications.Int J Mol Sci. 2021 Sep 5;22(17):9615. doi: 10.3390/ijms22179615. Int J Mol Sci. 2021. PMID: 34502524 Free PMC article. Review.
Cited by
-
Structure-function analysis of the role of megakaryoblastic leukemia 1 in megakaryocyte polyploidization.Haematologica. 2022 Dec 1;107(12):2972-2976. doi: 10.3324/haematol.2021.280499. Haematologica. 2022. PMID: 36453520 Free PMC article. No abstract available.
-
Differential regulation of cranial and cardiac neural crest by serum response factor and its cofactors.Elife. 2022 Jan 19;11:e75106. doi: 10.7554/eLife.75106. Elife. 2022. PMID: 35044299 Free PMC article.
-
New function of a well-known promoter: Enhancer activity of minimal CMV promoter enables efficient dual-cassette transgene expression.J Gene Med. 2021 Nov;23(11):e3380. doi: 10.1002/jgm.3380. Epub 2021 Aug 18. J Gene Med. 2021. PMID: 34318559 Free PMC article.
-
MRTFA: A critical protein in normal and malignant hematopoiesis and beyond.J Biol Chem. 2021 Jan-Jun;296:100543. doi: 10.1016/j.jbc.2021.100543. Epub 2021 Mar 13. J Biol Chem. 2021. PMID: 33722605 Free PMC article. Review.
-
Role of Rho-GTPases in megakaryopoiesis.Small GTPases. 2021 Sep-Nov;12(5-6):399-415. doi: 10.1080/21541248.2021.1885134. Epub 2021 Feb 11. Small GTPases. 2021. PMID: 33570449 Free PMC article. Review.
References
-
- Miano JM. Serum response factor: toggling between disparate programs of gene expression. J Mol Cell Cardiol. 2003;35(6):577–593. - PubMed
-
- Price MA, Hill C, Treisman R. Integration of growth factor signals at the c-fos serum response element. Philos Trans R Soc Lond B Biol Sci. 1996;351(1339):551–559. - PubMed
-
- Hill CS, Wynne J, Treisman R. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell. 1995;81(7):1159–1170. - PubMed
Publication types
MeSH terms
Substances
Associated data
- Actions
Grants and funding
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Research Materials
Miscellaneous