| First Author | Xie S | Year | 2021 |
| Journal | Sci Rep | Volume | 11 |
| Issue | 1 | Pages | 291 |
| PubMed ID | 33431926 | Mgi Jnum | J:300290 |
| Mgi Id | MGI:6502324 | Doi | 10.1038/s41598-020-79416-6 |
| Citation | Xie S, et al. (2021) The role of the PIK3CA gene in the development and aging of the brain. Sci Rep 11(1):291 |
| abstractText | The CLOVES syndrome is an overgrowth disease arising from mosaic activating somatic mutations in the PIK3CA gene. These mutations occur during fetal development producing malformation and overgrowth of a variety of tissues. It has recently been shown that treatment with low doses of a selective inhibitor of Class I PI3K catalytic subunit p110alpha, the protein product of the PIK3CA gene, can yield dramatic therapeutic benefits for patients with CLOVES and PROS (a spectrum of PIK3CA-related overgrowth syndromes). To assess the long-term effects of moderate loses of p110alpha activity, we followed development and growth of mice with heterozygous loss of p110alpha (Pik3ca(+/-)) over their entire lifetimes, paying particular attention to effects on the brain. While homozygous deletion of the Pik3ca gene is known to result in early embryonic lethality, these Pik3ca(+/-) mice displayed a longer lifespan compared to their wild-type littermates. These mice appeared normal, exhibited no obvious behavioral abnormalities, and no body weight changes. However, their brains showed a significant reduction in size and weight. Notably, mice featuring deletion of one allele of Pik3ca only in the brain also showed gradually reduced brain size and weight. Mechanistically, either deletion of p110alpha or pharmacological inhibition of p110alpha activity reduced neurosphere size, but not numbers, in vitro, suggesting that p110alpha activity is critical for neuronal stem cells. The phenotypes observed in our two genetically engineered mouse models suggest that the sustained pharmacological inhibition of the PIK3CA activity in human patients might have both beneficial and harmful effects, and future treatments may need to be deployed in a way to avoid or minimize adverse effects. |
