title: Pleiotropic platelet defects in mice with disrupted FOG1-NuRD interaction.
abstract: Understanding platelet biology has been aided by studies of mice with mutations in key megakaryocytic transcription factors. We have shown that point mutations in the GATA1 cofactor FOG1 that disrupt binding to the nucleosome remodeling and deacetylase (NuRD) complex have erythroid and megakaryocyte lineages defects. Mice that are homozygous for a FOG1 point mutation (ki/ki), which ablates FOG1-NuRD interactions, have platelets that display a gray platelet syndrome (GPS)-like macrothrombocytopenia. These platelets have few α-granules and an increased number of lysosomal-like vacuoles on electron microscopy, reminiscent of the platelet in patients with GATA1-related X-linked GPS. Here we further characterized the platelet defect in ki/ki mice. We found markedly deficient levels of P-selectin protein limited to megakaryocytes and platelets. Other α-granule proteins were expressed at normal levels and were appropriately localized to α-granule-like structures. Treatment of ki/ki platelets with thrombin failed to stimulate Akt phosphorylation, resulting in poor granule secretion and platelet aggregation. These studies show that disruption of the GATA1/FOG1/NuRD transcriptional system results in a complex, pleiotropic platelet defect beyond GPS-like macrothrombocytopenia and suggest that this transcriptional complex regulates not only megakaryopoiesis but also α-granule generation and signaling pathways required for granule secretion.
authors: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Yuhuan
authors: Y
authors: Wang
authors: Ronghua
authors: R
authors: Meng
authors: Vincent
authors: V
authors: Hayes
authors: Rudy
authors: R
authors: Fuentes
authors: Xiang
authors: X
authors: Yu
authors: Charles S
authors: CS
authors: Abrams
authors: Harry F G
authors: HF
authors: Heijnen
authors: Gerd A
authors: GA
authors: Blobel
authors: Michael S
authors: MS
authors: Marks
authors: Mortimer
authors: M
authors: Poncz
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D004195:Disease Models, Animal; D055652:Gray Platelet Syndrome / Q000235:genetics* / Q000378:metabolism; D008533:Megakaryocytes / Q000502:physiology; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D019007:P-Selectin / Q000235:genetics; D017354:Point Mutation / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D034061:Thrombopoiesis / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D019007:P-Selectin; D014157:Transcription Factors; C107310:Zfpm1 protein, mouse; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex