# Maternal undernutrition inhibits fetal rumen development: novel miRNA-736-mediated dual targeting of E2F2 and MYBL2 in sheep

## TL;DR

Maternal undernutrition harms fetal rumen development in male sheep by increasing miR-736, which targets genes that control cell growth and survival.

## Contribution

The study identifies miR-736 as a novel mediator of fetal rumen developmental deficits caused by maternal undernutrition.

## Key findings

- Maternal undernutrition reduces fetal rumen weight and papilla dimensions in male sheep.
- miR-736 overexpression targets E2F2 and MYBL2, leading to reduced cell cycle progression and increased apoptosis in rumen cells.
- Nutritional recovery partially restores metabolism but does not fully reverse developmental inhibition.

## Abstract

Undernutrition disrupts pregnant ewe’s metabolic homeostasis and severely inhibits fetal growth and development. In this study, undernourished and nutrition-recovery pregnant sheep models and rumen epithelial cells were utilized to investigate the mechanisms behind undernutrition-induced disruptions in male fetal rumen metabolism and development.

Maternal undernutrition significantly reduced male fetal rumen weight and papilla length, width and surface area. Maternal undernutrition extremely suppressed nutrient metabolism and energy production in male fetal rumen via JAK3/STAT3 signaling to inhibit cell cycle progression and male fetal rumen development, while maternal nutritional recovery partially restored metabolic inhibition but failed to alleviate male fetal rumen development. Meanwhile, 64 differentially expressed miRNAs (DEMs) were identified in male fetal rumen between undernourished ewes and controls. Novel miR-736 was overexpressed both in male fetal rumen of undernourished and nutrition-recovery models. E2F transcription factor 2 (E2F2) and MYB proto-oncogene like 2 (MYBL2) were the intersection of male fetal rumen differentially expressed genes (DEGs) and DEMs target genes integrated analysis and were predicted as novel miR-736 target genes. Further, we confirmed that novel miR-736 targeted and downregulated E2F2 and MYBL2 expression levels. Silencing E2F2 and MYBL2 promoted apoptosis and inhibited S-phase entry in rumen epithelial cells.

In summary, maternal undernutrition disrupted male fetal rumen metabolism and elevated novel miR-736, which targeted and downregulated E2F2 and MYBL2 to inhibit cell cycle progression and promote apoptosis, finally inhibited male fetal rumen development. This study provides new insights into the epigenetic mechanisms underlying maternal undernutrition-induced male fetal rumen developmental deficits.

The online version contains supplementary material available at 10.1186/s40104-025-01321-7.