Sp1/Sp3 transcription factors regulate hallmarks of megakaryocyte maturation and platelet formation and function.
Blood
; 125(12): 1957-67, 2015 Mar 19.
Article
en En
| MEDLINE
| ID: mdl-25538045
ABSTRACT
Sp1 and Sp3 belong to the specificity proteins (Sp)/Krüppel-like transcription factor family. They are closely related, ubiquitously expressed, and recognize G-rich DNA motifs. They are thought to regulate generic processes such as cell-cycle and growth control, metabolic pathways, and apoptosis. Ablation of Sp1 or Sp3 in mice is lethal, and combined haploinsufficiency results in hematopoietic defects during the fetal stages. Here, we show that in adult mice, conditional pan-hematopoietic (Mx1-Cre) ablation of either Sp1 or Sp3 has minimal impact on hematopoiesis, whereas the simultaneous loss of Sp1 and Sp3 results in severe macrothrombocytopenia. This occurs in a cell-autonomous manner as shown by megakaryocyte-specific (Pf4-Cre) double-knockout mice. We employed flow cytometry, cell culture, and electron microscopy and show that although megakaryocyte numbers are normal in bone marrow and spleen, they display a less compact demarcation membrane system and a striking inability to form proplatelets. Through megakaryocyte transcriptomics and platelet proteomics, we identified several cytoskeleton-related proteins and downstream effector kinases, including Mylk, that were downregulated upon Sp1/Sp3 depletion, providing an explanation for the observed defects in megakaryopoiesis. Supporting this notion, selective Mylk inhibition by ML7 affected proplatelet formation and stabilization and resulted in defective ITAM receptor-mediated platelet aggregation.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Plaquetas
/
Megacariocitos
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Factor de Transcripción Sp1
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Factor de Transcripción Sp3
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Blood
Año:
2015
Tipo del documento:
Article