Related Experiment Video
Updated: Mar 16, 2026
Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects
Mee Rie Sheen1, Sandra L Warner2, Jennifer L Fields2
1Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, United States.
Abstract:
The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many important cellular functions. The functional impact of deregulating the PIK3CA gene, 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 of p110α (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 of p110α 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 demonstrate the importance of tight regulation of PI3K signaling during embryonic vasculogenesis/angiogenesis..
Insights
Tight regulation of phosphatidylinositol 3-kinase (PI3K) signaling is crucial for embryonic development. Constitutive PI3K activation disrupts embryonic vascularization, leading to developmental lethality.
Area of Science:
- Molecular Biology
- Developmental Biology
- Cancer Biology
Background:
- The phosphatidylinositol 3-kinase (PI3K) pathway is vital for cellular functions.
- Gain-of-function mutations in PIK3CA, encoding the p110α subunit, are common in cancers.
- Dysregulation of PI3K signaling impacts various biological processes.
Purpose of the Study:
- To investigate the impact of constitutively active PI3K signaling on embryonic development.
- To elucidate the role of PI3K pathway regulation in vasculogenesis and angiogenesis.
Main Methods:
- Generation of a mouse model with inducible, constitutively active myristoylated p110α (myr-p110α).
- Utilized Cre-lox system for inducible gene expression.
- Observed embryonic development and morphology in transgenic mice.
Main Results:
- Constitutive PI3K activation in all cells led to embryonic lethality.
- Transgenic embryos exhibited morphological malformations, poor vascular development, dilated blood vessels, and hemorrhage.
- Both loss and constitutive activation of p110α disrupt embryonic vascular development.
Conclusions:
- Emphasize the critical importance of tightly regulated PI3K signaling during embryonic vasculogenesis and angiogenesis.
- Demonstrate that aberrant PI3K activation, similar to its loss, severely impacts embryonic vascular development.
- Highlight the PI3K pathway's essential role in maintaining vascular integrity during embryogenesis.
More Related Videos
10:39Functional Manipulation of Maternal Gene Products Using In Vitro Oocyte Maturation in Zebrafish
Published on: April 22, 2017
10:57Using In Vivo and Tissue and Cell Explant Approaches to Study the Morphogenesis and Pathogenesis of the Embryonic and Perinatal Aorta
Published on: September 12, 2017
Related Concept Videos
01:07Teratogenicity
02:41Lethal Alleles
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...