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|Title:||The RNA-binding protein SRSF3 has an essential role in megakaryocyte maturation and platelet production.||Austin Authors:||Heazlewood, Shen Y;Ahmad, Tanveer;Mohenska, Monika;Guo, Belinda B;Gangatirkar, Pradnya;Josefsson, Emma C;Ellis, Sarah L;Ratnadiwakara, Madara;Cao, Huimin;Cao, Benjamin;Heazlewood, Chad K;Williams, Brenda;Fulton, Madeline;White, Jacinta F;Ramialison, Mirana;Nilsson, Susan K;Änkö, Minna-Liisa||Affiliation:||Australian Regenerative Medicine Institute, Monash University, VIC, Australia..
Department of Molecular and Translational Sciences, Monash University, VIC, Australia..
Hudson Institute of Medical Research, VIC, Australia..
Olivia Newton-John Cancer Research Institute
Biomedical Manufacturing CSIRO, VIC, Australia..
Peter MacCallum Cancer Centre, and Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, Australia..
Department of Medical Biology, The University of Melbourne, VIC, Australia..
Walter and Eliza Hall Institute of Medical Research, VIC, Australia..
School of Biomedical Sciences, Pathology and Laboratory Science, University of Western Australia, WA, Australia..
|Issue Date:||3-Mar-2022||Publication information:||Blood 2022; 139(9): 1359-1373||Abstract:||RNA processing is increasingly recognized as a critical control point in the regulation of different hematopoietic lineages including megakaryocytes responsible for the production of platelets. Platelets are anucleate cytoplasts that contain a rich repertoire of RNAs encoding proteins with essential platelet functions derived from the parent megakaryocyte. It is largely unknown how RNA binding proteins contribute to the development and functions of megakaryocytes and platelets. We show that serine-arginine-rich splicing factor 3 (SRSF3) is essential for megakaryocyte maturation and generation of functional platelets. Megakaryocyte-specific deletion of Srsf3 in mice led to macrothrombocytopenia characterized by megakaryocyte maturation arrest, dramatically reduced platelet counts, and abnormally large functionally compromised platelets. SRSF3 deficient megakaryocytes failed to reprogram their transcriptome during maturation and to load platelets with RNAs required for normal platelet function. SRSF3 depletion led to nuclear accumulation of megakaryocyte mRNAs, demonstrating that SRSF3 deploys similar RNA regulatory mechanisms in megakaryocytes as in other cell types. Our study further suggests that SRSF3 plays a role in sorting cytoplasmic megakaryocyte RNAs into platelets and demonstrates how SRSF3-mediated RNA processing forms a central part of megakaryocyte gene regulation. Understanding SRSF3 functions in megakaryocytes and platelets provides key insights into normal thrombopoiesis and platelet pathologies as SRSF3 RNA targets in megakaryocytes are associated with platelet diseases.||URI:||https://ahro.austin.org.au/austinjspui/handle/1/29075||DOI:||10.1182/blood.2021013826||ORCID:||0000-0001-5910-2309
|Journal:||Blood||PubMed URL:||34852174||PubMed URL:||https://pubmed.ncbi.nlm.nih.gov/34852174/||Type:||Journal Article|
|Appears in Collections:||Journal articles|
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