Abstract
The Pik3c3 gene encodes an 887 amino acid lipid kinase, phosphoinositide-3-kinase class 3 (PIK3C3). PIK3C3 is known to regulate various intracellular membrane trafficking events. However, little is known about its functions during early embryogenesis in mammals. To investigate the function of PIK3C3 in vivo, we generated Pik3c3 null mice. We show here that Pik3c3 heterozygous are normal and fertile. In contrast, Pik3c3 homozygous mutants are embryonic lethal and die between E7.5 and E8.5 of embryogenesis. Mutant embryos are poorly developed with no evidence of mesoderm formation, and suffer from severely reduced cell proliferations. Cell proliferation defect is also evident in vitro, where mutant blastocysts in culture fail to give rise to typical colonies formed by inner cell mass. Electron microscopic analysis revealed that epiblast cells in mutant embryos appear normal, whereas the visceral endoderm cells contain larger vesicles inside the lipid droplets. Finally, we provide evidence that mTOR signaling is drastically reduced in Pik3c3 null embryos, which could be a major contributor to the observed proliferation and embryogenesis defects.
Highlights
In mammals, there are three classes of phosphoinositide-3kinases (PI3Ks)
The most prominent defect caused by Pik3c3 deletion is a severely reduced embryonic cell proliferation
The death of Pik3c3 mutant embryos prior to gastrulation is likely due to the lack of proliferative burst required for the development of different germ layers
Summary
Most of the previous studies on the in vivo role of PI3Ks focused on class I PI3Ks, which were shown to be required for early embryonic development [1,2,3]. The role of the class III PI3K, PIK3C3 ( called Vps34), during mammalian development is not known. PIK3C3/Vps represents the most ancient form of PI3Ks and is the only PI3K in yeast [4]. Previous studies have shown that PIK3C3 regulates several membrane trafficking events including homotypical fusion between early endosomes [5,6,7], bi-directional transportation of early endosomes along the microtubules [8,9], maturation of endosomes or phagosomes [10,11,12,13], biogenesis of multivesicular bodies [14,15] and retrograde transportation from endosomes to the Golgi apparatus [16,17]. PIK3C3 is shown to be required for nutrient/amino acid mediated activation of mTOR signaling in cultured cells [23,24,25,26]
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