Novel role for PI3Kβ in placental function through regulation of system A amino acid transporter expression, associated with embryonic lethality

TL;DR

A new role for PI3Kβ in placental function is discovered, linking it to amino acid transport and embryonic growth.

Contribution

Identifies a novel role for p110β in regulating system A amino acid transporters in the placenta.

Findings

p110β kinase-dead embryos show placental insufficiency and reduced system A amino acid transporter expression.

Defective amino acid transfer is linked to embryonic growth restriction and partial lethality.

p110β's role is more critical during development than in adult physiology.

Abstract

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. p110β 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 p110β remain unclear. While homozygous p110β 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 p110β kinase-dead embryos, revealing a previously unrecognised role for p110β in controlling the expression of system A amino acid transporters. We show that homozygous p110β 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 p110β kinase-dead embryos. This predominantly embryonic p110β 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 p110β in development than in adult homeostasis may also help explain why p110β inhibitors, compared to inhibitors of other PI3K isoforms, are well-tolerated in adults.

The online version contains supplementary material available at 10.1007/s00018-025-05937-w.

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