Prader-Willi syndrome genes are expressed in placenta and play a role in function

Technical Summary

Problem
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by abnormal feeding behaviors, caused by the loss of paternally derived gene expression within the imprinted interval on chromosome 15q11-q13. While the post-natal manifestations are well-documented, the developmental origins of these feeding-related phenotypes remain unclear. Recent hypotheses suggest that these behaviors may be developmentally programmed in utero through compromised placental function, yet the specific role of PWS-associated genes in placental biology has not been fully established.

Methodology
To investigate the expression and function of PWS genes in the placenta, the authors employed a multi-faceted approach using mouse models. First, they examined the spatial expression patterns of PWS genes in the mouse placenta, specifically focusing on the labyrinth zone, which is central to nutrient transport. They utilized immunohistochemistry to co-localize specific PWS transcripts with Kdr-positive fetal endothelial cells. Second, the study utilized a novel PWS deletion mouse model, designated as Large+/-, which mimics the human PWS deletion. In this model, the authors assessed the expression levels of PWS genes within the placenta and quantified the population of Kdr-positive fetal endothelial cells. Finally, they evaluated fetal growth parameters late in gestation to determine the physiological impact of these cellular and molecular changes.

Key Contributions and Results
The study provides the first evidence that several PWS-associated genes are actively expressed in the mouse placenta. Specifically, the transcripts Magel2, Necdin, and the long non-coding RNA Sngh14 were found to co-localize with Kdr-positive fetal endothelial cells within the labyrinth zone.

In the Large+/- mouse model, the researchers observed a marked reduction in the expression of these PWS genes in the placenta. This molecular deficit was associated with a significant (~25%) reduction in the number of Kdr-positive fetal endothelial cells. Despite this substantial loss of endothelial cells, the study noted that fetal growth late in gestation was not significantly reduced in the mutant model.

Significance
The paper concludes that while the reduction in fetal endothelial cells did not result in an immediate, statistically significant decrease in fetal growth during late gestation, the data strongly suggest that placental function and nutrient transfer from mother to fetus are compromised in PWS. The authors posit that these early developmental disruptions in placental efficiency may contribute to the post-natal phenotypes observed in PWS, supporting the hypothesis that the disorder's characteristic feeding behaviors are, in part, programmed in utero via abnormal placental function.