Defective tubulin organization and proplatelet formation in murine megakaryocytes lacking Rac1 and Cdc42.
Blood
; 122(18): 3178-87, 2013 Oct 31.
Article
em En
| MEDLINE
| ID: mdl-23861250
ABSTRACT
Blood platelets are anuclear cell fragments that are essential for blood clotting. Platelets are produced by bone marrow megakaryocytes (MKs), which extend protrusions, or so-called proplatelets, into bone marrow sinusoids. Proplatelet formation requires a profound reorganization of the MK actin and tubulin cytoskeleton. Rho GTPases, such as RhoA, Rac1, and Cdc42, are important regulators of cytoskeletal rearrangements in platelets; however, the specific roles of these proteins during platelet production have not been established. Using conditional knockout mice, we show here that Rac1 and Cdc42 possess redundant functions in platelet production and function. In contrast to a single-deficiency of either protein, a double-deficiency of Rac1 and Cdc42 in MKs resulted in macrothrombocytopenia, abnormal platelet morphology, and impaired platelet function. Double-deficient bone marrow MKs matured normally in vivo but displayed highly abnormal morphology and uncontrolled fragmentation. Consistently, a lack of Rac1/Cdc42 virtually abrogated proplatelet formation in vitro. Strikingly, this phenotype was associated with severely defective tubulin organization, whereas actin assembly and structure were barely affected. Together, these results suggest that the combined action of Rac1 and Cdc42 is crucial for platelet production, particularly by regulating microtubule dynamics.
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Base de dados:
MEDLINE
Assunto principal:
Tubulina (Proteína)
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Megacariócitos
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Proteína cdc42 de Ligação ao GTP
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Proteínas rac1 de Ligação ao GTP
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Células Progenitoras de Megacariócitos
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article