Argonaute2 modulates megakaryocyte development and sex-specific control of platelet protein expression and reactivity
Abstract Platelets are enriched in miRNAs and harbor Ago2 as the principal RNA silencing Argonaute. However, roles in thrombopoiesis and platelet function remain poorly understood. We generated megakaryocyte/platelet-specific Ago2-deleted (Ago2 KO) mice and assessed proteomic and functional effects....
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-88106-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832571649034027008 |
|---|---|
| author | Sophia Lazar Jeremy G.T. Wurtzel Shayan Askari Matthew Cooper Xuefei Zhao Peisong Ma Lawrence E. Goldfinger |
| author_facet | Sophia Lazar Jeremy G.T. Wurtzel Shayan Askari Matthew Cooper Xuefei Zhao Peisong Ma Lawrence E. Goldfinger |
| author_sort | Sophia Lazar |
| collection | DOAJ |
| description | Abstract Platelets are enriched in miRNAs and harbor Ago2 as the principal RNA silencing Argonaute. However, roles in thrombopoiesis and platelet function remain poorly understood. We generated megakaryocyte/platelet-specific Ago2-deleted (Ago2 KO) mice and assessed proteomic and functional effects. We predicted platelet hyperreactivity with Ago2 deletion due to large-scale upregulated protein expression. Platelet counts were normal. Mean volumes were increased, associated with larger, though fewer megakaryocytes. Ago2-deleted platelets from male mice showed hyperreactivity to thromboxane but not to other agonists compared to controls, whereas Ago2-deleted platelets from female mice showed normal reactivity. Ago2 KO mice displayed normal hemostasis and clot dynamics. Proteomes of Ago2-deleted and wild type platelets were mostly similar. However, Ago1 - undetectable in wild type platelets - was upregulated in Ago2-deleted platelets in both males and females, confirmed by immunoblotting. Female Ago2-deleted platelets selectively showed downregulation of a protein cohort established in breast cancer cells to be transcriptionally regulated by estrogen receptor-beta coupled to Ago2, whereas male Ago2-deleted platelets did not. Thus, Ago2 is important for platelet development and function, putatively partially rescued by upregulation of Ago1. Platelet reactivity controlled by Ago2 reflects sex-specific regulation of gene expression potentially at both transcriptional and translational levels in megakaryocytes and platelets. |
| format | Article |
| id | doaj-art-468a4d1817fc40a088b3c612d1da595d |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-468a4d1817fc40a088b3c612d1da595d2025-02-02T12:24:13ZengNature PortfolioScientific Reports2045-23222025-01-0115111410.1038/s41598-025-88106-0Argonaute2 modulates megakaryocyte development and sex-specific control of platelet protein expression and reactivitySophia Lazar0Jeremy G.T. Wurtzel1Shayan Askari2Matthew Cooper3Xuefei Zhao4Peisong Ma5Lawrence E. Goldfinger6Department of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson UniversityDepartment of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson UniversityAbstract Platelets are enriched in miRNAs and harbor Ago2 as the principal RNA silencing Argonaute. However, roles in thrombopoiesis and platelet function remain poorly understood. We generated megakaryocyte/platelet-specific Ago2-deleted (Ago2 KO) mice and assessed proteomic and functional effects. We predicted platelet hyperreactivity with Ago2 deletion due to large-scale upregulated protein expression. Platelet counts were normal. Mean volumes were increased, associated with larger, though fewer megakaryocytes. Ago2-deleted platelets from male mice showed hyperreactivity to thromboxane but not to other agonists compared to controls, whereas Ago2-deleted platelets from female mice showed normal reactivity. Ago2 KO mice displayed normal hemostasis and clot dynamics. Proteomes of Ago2-deleted and wild type platelets were mostly similar. However, Ago1 - undetectable in wild type platelets - was upregulated in Ago2-deleted platelets in both males and females, confirmed by immunoblotting. Female Ago2-deleted platelets selectively showed downregulation of a protein cohort established in breast cancer cells to be transcriptionally regulated by estrogen receptor-beta coupled to Ago2, whereas male Ago2-deleted platelets did not. Thus, Ago2 is important for platelet development and function, putatively partially rescued by upregulation of Ago1. Platelet reactivity controlled by Ago2 reflects sex-specific regulation of gene expression potentially at both transcriptional and translational levels in megakaryocytes and platelets.https://doi.org/10.1038/s41598-025-88106-0miRNAArgonauteRISCProteomicsHemostasisMegakaryocyte |
| spellingShingle | Sophia Lazar Jeremy G.T. Wurtzel Shayan Askari Matthew Cooper Xuefei Zhao Peisong Ma Lawrence E. Goldfinger Argonaute2 modulates megakaryocyte development and sex-specific control of platelet protein expression and reactivity Scientific Reports miRNA Argonaute RISC Proteomics Hemostasis Megakaryocyte |
| title | Argonaute2 modulates megakaryocyte development and sex-specific control of platelet protein expression and reactivity |
| title_full | Argonaute2 modulates megakaryocyte development and sex-specific control of platelet protein expression and reactivity |
| title_fullStr | Argonaute2 modulates megakaryocyte development and sex-specific control of platelet protein expression and reactivity |
| title_full_unstemmed | Argonaute2 modulates megakaryocyte development and sex-specific control of platelet protein expression and reactivity |
| title_short | Argonaute2 modulates megakaryocyte development and sex-specific control of platelet protein expression and reactivity |
| title_sort | argonaute2 modulates megakaryocyte development and sex specific control of platelet protein expression and reactivity |
| topic | miRNA Argonaute RISC Proteomics Hemostasis Megakaryocyte |
| url | https://doi.org/10.1038/s41598-025-88106-0 |
| work_keys_str_mv | AT sophialazar argonaute2modulatesmegakaryocytedevelopmentandsexspecificcontrolofplateletproteinexpressionandreactivity AT jeremygtwurtzel argonaute2modulatesmegakaryocytedevelopmentandsexspecificcontrolofplateletproteinexpressionandreactivity AT shayanaskari argonaute2modulatesmegakaryocytedevelopmentandsexspecificcontrolofplateletproteinexpressionandreactivity AT matthewcooper argonaute2modulatesmegakaryocytedevelopmentandsexspecificcontrolofplateletproteinexpressionandreactivity AT xuefeizhao argonaute2modulatesmegakaryocytedevelopmentandsexspecificcontrolofplateletproteinexpressionandreactivity AT peisongma argonaute2modulatesmegakaryocytedevelopmentandsexspecificcontrolofplateletproteinexpressionandreactivity AT lawrenceegoldfinger argonaute2modulatesmegakaryocytedevelopmentandsexspecificcontrolofplateletproteinexpressionandreactivity |