nitrophenols and Hemorrhage

Mature megakaryocytes depend on the function of Bcl-x(L), a member of the Bcl-2 family of prosurvival proteins, to proceed safely through the process of platelet shedding. Despite this, loss of Bcl-x(L) does not prevent the growth and maturation of megakaryocytes, suggesting redundancy with other prosurvival proteins. We therefore generated mice with a megakaryocyte-specific deletion of Mcl-1, which is known to be expressed in megakaryocytes. Megakaryopoiesis, platelet production, and platelet lifespan were unperturbed in Mcl-1(Pf4Δ/Pf4Δ) animals. However, treatment with ABT-737, a BH3 mimetic compound that inhibits the prosurvival proteins Bcl-2, Bcl-x(L), and Bcl-w resulted in the complete ablation of megakaryocytes and platelets. Genetic deletion of both Mcl-1 and Bcl-x(L) in megakaryocytes resulted in preweaning lethality. Megakaryopoiesis in Bcl-x(Pf4Δ/Pf4Δ) Mcl-1(Pf4Δ/Pf4Δ) embryos was severely compromised, and these animals exhibited ectopic bleeding. Our studies indicate that the combination of Bcl-x(L) and Mcl-1 is essential for the viability of the megakaryocyte lineage.

Topics: Alleles; Animals; bcl-X Protein; Biphenyl Compounds; Blood Cell Count; Blood Platelets; Cell Count; Cell Death; Cell Size; Cell Survival; Dose-Response Relationship, Drug; Embryo, Mammalian; Fetus; Gene Deletion; Hemorrhage; Liver; Lymphatic Vessels; Megakaryocytes; Mice; Mice, Inbred C57BL; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Organ Specificity; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Thrombopoiesis

Topics: 2,4-Dinitrophenol; Barbiturates; Brain; Chlorpromazine; Cyanides; Dinitrophenols; Glutamine; Hemorrhage; In Vitro Techniques; Nitrophenols; Salicylanilides; Salicylates