title: Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification.
abstract: The NOTCH signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. However, the molecular basis for its role at the different steps of stem cell lineage commitment is unclear. We recently identified the NOTCH signaling pathway as a positive regulator of megakaryocyte lineage specification during hematopoiesis, but the developmental pathways that allow hematopoietic stem cell differentiation into the erythro-megakaryocytic lineages remain controversial. Here, we investigated the role of downstream mediators of NOTCH during megakaryopoiesis and report crosstalk between the NOTCH and PI3K/AKT pathways. We demonstrate the inhibitory role of phosphatase with tensin homolog and Forkhead Box class O factors on megakaryopoiesis in vivo. Finally, our data annotate developmental mechanisms in the hematopoietic system that enable a decision to be made either at the hematopoietic stem cell or the committed progenitor level to commit to the megakaryocyte lineage, supporting the existence of 2 distinct developmental pathways.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Cornejo
authors.forename: Vinciane
authors.initials: V
authors.lastname: Mabialah
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Sykes
authors.forename: Tulasi
authors.initials: T
authors.lastname: Khandan
authors.forename: Cristina
authors.initials: C
authors.lastname: Lo Celso
authors.forename: Cécile K
authors.initials: CK
authors.lastname: Lopez
authors.forename: Paola
authors.initials: P
authors.lastname: Rivera-Muñoz
authors.forename: Philippe
authors.initials: P
authors.lastname: Rameau
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tothova
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercher
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D019070:Cell Lineage / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008533:Megakaryocytes / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020239:Receptor Cross-Talk / Q000502:physiology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D034061:Thrombopoiesis / Q000235:genetics
chemical_list: D051858:Forkhead Transcription Factors; D051880:Receptors, Notch; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase