title: Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects.
abstract: The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many important cellular functions. The functional impact of deregulating thePIK3CAgene, encoding the p110α catalytic subunit of PI3K, is validated by frequent gain of function mutations in a range of human cancers. We generated a mouse model with an inducible constitutively active form of PI3K. In this model Cre recombinase activates expression of a myristoylated form ofp110α (myr-p110α). The myristoylated version of p110α brings the protein to the cytoplasmic side of the cell membrane, which mimics the normal activation mechanism for the p110α catalytic subunit and activates the PI3K enzyme. Constitutively activated PI3K signaling induced by myr-p110α in all cells of the developing mouse caused lethality during embryonic development. Transgenic Cre;myr-p110α heterozygous embryos displayed morphological malformation and poor vascular development with extremely dilated blood vessels and hemorrhage in the embryo and the extraembryonic yolk sac. Previous studies demonstrated that loss ofp110α during embryonic development causes angiogenic disruption and here we show that constitutive activation of p110α by gain of function mutation during development also disrupts vasculogenesis/angiogenesis in what appears to be a similar manner.These finding demonstratethe importance of tight regulation ofPI3K signaling during embryonicvasculogenesis/angiogenesis..
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, United States.
authors.forename: Mee Rie
authors.initials: MR
authors.lastname: Sheen
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, United States; Norris Cotton Cancer Center, Lebanon, NH 03756, United States.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Warner
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, United States; Norris Cotton Cancer Center, Lebanon, NH 03756, United States.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Fields
authors.affiliation: umor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, United States.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, United States; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Fiering
keywords: Cre recombinase; PIK3CA; angiogenesis; embryonic development; hemorrhage; lethality; morphological malformation; myristoylated; p110α; vasculogenesis