| First Author | Beauchemin H | Year | 2017 |
| Journal | Haematologica | Volume | 102 |
| Issue | 3 | Pages | 484-497 |
| PubMed ID | 28082345 | Mgi Jnum | J:274515 |
| Mgi Id | MGI:6295279 | Doi | 10.3324/haematol.2016.150375 |
| Citation | Beauchemin H, et al. (2017) Gfi1b controls integrin signaling-dependent cytoskeleton dynamics and organization in megakaryocytes. Haematologica 102(3):484-497 |
| abstractText | Mutations in GFI1B are associated with inherited bleeding disorders called GFI1B-related thrombocytopenias. We show here that mice with a megakaryocyte-specific Gfi1b deletion exhibit a macrothrombocytopenic phenotype along a megakaryocytic dysplasia reminiscent of GFI1B-related thrombocytopenia. GFI1B deficiency increases megakaryocyte proliferation and affects their ploidy, but also abrogates their responsiveness towards integrin signaling and their ability to spread and reorganize their cytoskeleton. Gfi1b-null megakaryocytes are also unable to form proplatelets, a process independent of integrin signaling. GFI1B-deficient megakaryocytes exhibit aberrant expression of several components of both the actin and microtubule cytoskeleton, with a dramatic reduction of alpha-tubulin. Inhibition of FAK or ROCK, both important for actin cytoskeleton organization and integrin signaling, only partially restored their response to integrin ligands, but the inhibition of PAK, a regulator of the actin cytoskeleton, completely rescued the responsiveness of Gfi1b-null megakaryocytes to ligands, but not their ability to form proplatelets. We conclude that Gfi1b controls major functions of megakaryocytes such as integrin-dependent cytoskeleton organization, spreading and migration through the regulation of PAK activity whereas the proplatelet formation defect in GFI1B-deficient megakaryocytes is due, at least partially, to an insufficient alpha-tubulin content. |
