| First Author | Conduit SE | Year | 2025 |
| Journal | Cell Mol Life Sci | Volume | 82 |
| Issue | 1 | Pages | 413 |
| PubMed ID | 41258474 | Mgi Jnum | J:375476 |
| Mgi Id | MGI:8265462 | Doi | 10.1007/s00018-025-05937-w |
| Citation | Conduit SE, et al. (2025) Novel role for PI3Kbeta in placental function through regulation of system A amino acid transporter expression, associated with embryonic lethality. Cell Mol Life Sci 82(1):413 |
| abstractText | The placenta is essential for embryonic development, in part by mediating nutrient transfer from mother to embryo. Placental insufficiency is the most common cause of intrauterine growth restriction which has long-term health consequences lasting into adulthood. p110beta is a class IA phosphoinositide 3-kinase (PI3K) catalytic subunit, a family of lipid kinases which are critical regulators of adult metabolism, immunity and embryonic and placental development. However, unlike the other class IA PI3K isoforms, the in vivo functions of p110beta remain unclear. While homozygous p110beta kinase-dead mice are mostly embryonically lethal, some survive into adulthood with no apparent phenotypes, other than reduced fertility. The mechanism(s) underlying this embryonic lethality remain unclear. Therefore, we performed an in-depth characterisation of p110beta kinase-dead embryos, revealing a previously unrecognised role for p110beta in controlling the expression of system A amino acid transporters. We show that homozygous p110beta kinase-dead embryos are phenotypically normal, but growth-restricted and exhibit placental insufficiency. The placenta is small with a reduced nutrient storing junctional zone and downregulation of the system A amino acid transporters, required for maternal-to-embryo amino acid transfer. These data suggest defective amino acid transfer drives embryonic growth restriction and partial lethality of p110beta kinase-dead embryos. This predominantly embryonic p110beta phenotype is consistent with the notion that system A amino acid transporters are more critical during development than in adult physiology. The greater significance of p110beta in development than in adult homeostasis may also help explain why p110beta inhibitors, compared to inhibitors of other PI3K isoforms, are well-tolerated in adults. |
