Imprinted genes are a peculiar subset of the genome. Most genes are expressed from both the maternal and paternal copies, but imprinted genes carry chemical tags laid down in the egg or sperm that silence one copy entirely, leaving only the maternal or paternal version active. In the placenta, these parent-of-origin effects are thought to reflect evolutionary conflict: paternal genes tend to push for greater extraction of maternal resources, while maternal genes restrain fetal demands to preserve the mother’s ability to sustain current and future pregnancies. Phlda2, formally known as Pleckstrin Homology-Like Domain Family A Member 2, is one of the maternal army’s foot soldiers, normally expressed only from the chromosome inherited from the mother.

Researchers at Cardiff University, led by R. M. John together with colleagues including A. R. Isles, had previously shown that elevated Phlda2 expression, a state mimicking loss of imprinting in which the gene’s dosage is effectively doubled, produces placentas that secrete fewer hormones, fetuses that grow poorly, and mothers that neglect their pups after birth. Their earlier work on the paternally expressed gene Peg3 had already demonstrated that imprinted genes can act as master regulators of placental endocrine lineages and that disrupting them can produce sexually dimorphic outcomes, with males suffering more. The natural question was whether a maternally expressed gene would show the same pattern, or whether the sexes would flip.

To find out, the team crossed wildtype C57BL/6 female mice with transgenic males carrying an extra bacterial artificial chromosome copy of Phlda2, generating embryos that overexpressed the gene and thus modelled loss of imprinting. They then dissected the placenta at embryonic day 14.5, a critical window when the placenta’s endocrine machinery is being established, and collected fetal and placental weights at embryonic day 18.5, near the end of gestation.

The team used RNAscope, a high-resolution in situ hybridization technique, combined with classical histology to map the placenta’s specialized cell populations. The mouse placenta is organized into two major compartments. The labyrinth zone handles nutrient and gas exchange, while the junctional zone is the endocrine heart of the organ, packed with hormone-producing cells including the spongiotrophoblast layer, glycogen cells, and parietal trophoblast giant cells. The spongiotrophoblast in particular churns out a vast repertoire of prolactin-related hormones and pregnancy-specific glycoproteins that remodel the mother’s physiology, directing blood flow, nutrient mobilization, and even priming her brain for maternal care.

What the researchers saw was unambiguous. In placentas carrying the Phlda2 overexpression, the junctional zone lost a significant number of spongiotrophoblast cells, and the depletion was substantially more severe in female placentas than in male ones. Glycogen cells and parietal trophoblast giant cells were also reduced in number, but those losses were even-handed between the sexes. The sexual dimorphism was confined specifically to the spongiotrophoblast compartment, the very cell population responsible for the placenta’s most powerful endocrine output.

Molecular measurements backed up the cellular picture. Using reverse-transcription quantitative PCR and bulk RNA sequencing, the team found that genes encoding placental hormones normally produced by the spongiotrophoblast were downregulated in the mutant placentas, and once again the reduction was biased toward females. Gene set enrichment analysis reinforced the conclusion: the female mutant placenta showed a more profound dampening of its hormone-producing program than the male, despite both sexes carrying the identical genetic modification.

The most consequential result, however, appeared in the growth curves. At embryonic day 18.5, late in gestation, female fetuses with elevated Phlda2 expression were significantly growth restricted compared with their wildtype female littermates. Male fetuses carrying the same transgene showed no comparable reduction in weight. In other words, the genetic perturbation narrowed the female placenta’s endocrine signalling capacity, and the female fetus paid the price by growing more slowly, while the male fetus maintained its growth trajectory despite the same molecular insult.

The authors interpret this asymmetry through the lens of evolutionary theory about parental resource allocation. Phlda2 is known to be responsive to maternal adversity: when the mother experiences nutritional deficiency or other forms of prenatal stress, placental Phlda2 expression rises, and the resulting restraint on hormone production lowers the fetus’s demands on her body. The new findings suggest that this demand-dampening system is not symmetrical. Female fetuses appear to reduce their claims on the mother when Phlda2 signalling rises, effectively shrinking their own growth to spare maternal reserves. Male fetuses, by contrast, hold their ground, continuing to extract resources even under adverse conditions. Such sex-specific strategies could reflect the different reproductive payoffs that sons and daughters offer under variable environmental conditions, with parent-of-origin imprinting serving as the molecular lever that mediates the negotiation.

The translational implications are hard to ignore. In human pregnancies, elevated placental PHLDA2 has repeatedly been associated with fetal growth restriction and low birthweight, yet these clinical studies have generally not accounted for the sex of the infant. If, as the mouse data suggest, the gene’s effects on growth are sex-specific, then pooling male and female pregnancies may have obscured important patterns and muddied the interpretation of biomarker studies. The Cardiff team argues that fetal sex deserves routine consideration in research on imprinted genes and pregnancy complications, from intrauterine growth restriction to the long-term metabolic and behavioural consequences of prenatal adversity. The work, funded by the Biotechnology and Biological Sciences Research Council, adds Phlda2 to a growing list of imprinted genes, alongside Peg3, whose disruption produces sex-dimorphic placental and offspring phenotypes, and it strengthens the broader hypothesis that the placenta is not merely a passive conduit for nutrients but an active, sexually differentiated endocrine organ that negotiates the terms of maternal investment on the fetus’s behalf.

Subject of Research: Sex-specific effects of loss-of-imprinting of the maternally expressed gene Phlda2 on placental endocrine development and fetal growth in mice

Article Title: Sex-specific consequences of loss-of-imprinting of the maternally expressed gene Pleckstrin Homology-Like Domain Family A Member 2 (Phlda2) on placental development and fetal growth

Article References: Chibnall, A., Harrison, D. J., Lysikova, E., Malinoshevska, M., Stoddart, A., Perry, I. A., Christofides, S., Isles, A. R., & John, R. M. (2026). Sex-specific consequences of loss-of-imprinting of the maternally expressed gene Pleckstrin Homology-Like Domain Family A Member 2 (Phlda2) on placental development and fetal growth. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00972-z

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00972-z

Keywords: genomic imprinting, Phlda2, placenta, placental hormones, fetal growth restriction, sexual dimorphism, spongiotrophoblast, junctional zone, prenatal adversity, parent-of-origin effects, Biology of Sex Differences, Cardiff University