436 Regulation of brain-placental axis in mouse versus pig

Abstract Emerging evidence suggests that the placenta has key roles in the development of mammalian brain. The brain-placental axis refers to the molecular and cellular events by which the placenta programs the fetal brain development during reproduction and leaves a lasting influence on the health and disease of the brain later in life. Though most studies on the brain-placental axis have utilized mouse models, the pig, Sus scrofa, is now increasingly used as a large animal model to study brain diseases in humans. However, no study has been performed to understand the regulation of the brain-placental axis in a comparative manner between mouse and pig. In the present work, we performed a comparative analysis of single-nuclei gene expression patterns in the placenta and fetal brain between mouse and pig. The placenta and fetal brain cells expressing the common orthologous genes and the species-specific genes were identified in both species. The analysis showed that a relatively fewer number of cell clusters expressed genes in a correlated manner between the placenta and fetal brain of pig relative to that of mouse. The results further showed that specific genes related to visual perception were expressed in specific cell types of the fetal brain of both mouse and pig. These genes were expressed in a coordinated manner with a set of genes expressed in specific cell types of the placenta. Further analysis showed that these placental expressed genes were significantly differentially regulated (P < 0.05, fold changes > 2) in the term-placenta between nocturnal and diurnal animals. Significant enrichment (P < 0.05) of specific binding motifs of known transcription factors, whose functions are related to the specification of retinal cells, was observed in the immediate upstream region of these placenta genes. Phylogenetic analysis of these genes among 29 diverse mammalian species differing in placenta type and activity (nocturnal or diurnal) was performed. The Bayes Traits discrete trait correlation test using the inferred phylogenies and the known trait data identified genes associated with the correlated evolution (Log Bayes Factor > 2) of placenta with animal activity (nocturnal or diurnal). The functional association of these genes with visual perception was evident from differential expression in the ocular cells between pig and mouse. Together, the findings of this study show that the regulation of the brain-placental axis plays a role in the evolution of visual perception function of brain to shape the nocturnal or diurnal activity of placental animals. However, factors other than the brain-placental axis are also known to influence temporal changes in nocturnal or diurnal activity of specific animals. Thus, future studies, potentially applying experimental evolution approaches, are needed to dissect the mechanisms of nocturnal bottleneck in placental animals.