RNA processing regulates megakaryocytes and platelet production — ASN Events

RNA processing regulates megakaryocytes and platelet production (#190)

Tanveer Ahmad 1 2 3 , Shen Heazlewood 1 , Brenda Williams 1 , Jess Hatwell-Humble 1 , Monika Mohenska 2 3 4 , Mirana Ramialison 5 , Susie Nilsson 1 5 , Minna-Liisa Anko 2 3
  1. Manufacturing, CSIRO, Melbourne, VIC, Australia
  2. Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  3. Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
  4. Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
  5. Australian Regenerative Medicine Institute, Melbourne, VIC, Australia

Platelet deficiency (thrombocytopenia) is a common type of bone marrow failure, and a life-threatening condition caused by mutations, chemicals or infections that affect megakaryocytes, the platelet producing cells. The circulating platelets are specialised anuclear cells that are essential for blood clotting and haemostasis while the bone marrow megakaryocytes (MK) are large and morphologically distinct cells with a single polypoid nucleus. The molecular mechanisms involved in MK differentiation, maturation and subsequent platelet release are poorly understood. We have identified RNA binding protein SRSF3 (serine-arginine rich splicing factor 3) as a novel regulator within the haematopoietic system. Srsf3-Pf4-Cre mice that expresses Cre recombinase in MK, have severe thrombocytopenia, resulting in a 90% reduction in platelets compared to wildtype mice.  The ploidy distribution of the Srsf3 knockout MK is not affected and the MK number slightly increased. Srsf3-null high ploidy MK express significantly lower levels of the cell surface markers CD41 and CD61, suggesting MK dysfunction. RNA-sequencing analysis of low and high ploidy control and knockout MK suggests that SRSF3 plays a central role in the control of gene expression programs essential for MK function and platelet production. Bioinformatics analysis revealed that the high ploidy MK are particularly affected in the knockout mice. Currently, the specific RNA processing mechanisms regulated by SRSF3 in MK are investigated. We are also characterising the functionality and molecular level defects of the Srsf3 knockout platelets. These analyses will provide further insights into the role of SRSF3 in MK function and platelet homeostasis. Our unique mouse models will enhance the molecular level understanding of MK maturation and platelet biogenesis and may identify new avenues to tackle haematopoietic disorders in the future.

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