Single-Cell Transcriptional Response of the Placenta to the Ablation of Caveolin-1: Insights into the Adaptive Regulation of Brain-Placental Axis in Mice

Caveolin-1 ( ) is a major plasma membrane protein that plays important functions in cellular metabolism, proliferation, and senescence. Mice lacking show abnormal gene expression in the fetal brain. Though evidence for placental influence on brain development is emerging, whether the ablation of affects the regulation of the brain-placental axis remains unexamined. The current study tests the hypothesis that gene expression changes in specific cells of the placenta and the fetal brain are linked to the deregulation of the brain-placental axis in -null mice. By performing single-nuclei RNA sequencing (snRNA-seq) analyses, we show that the abundance of the extravillious trophoblast (EVT) and stromal cells, but not the cytotrophoblast (CTB) or syncytiotrophoblast (STB), are significantly impacted due to ablation in mice. Interestingly, specific genes related to brain development and neurogenesis were significantly differentially expressed in trophoblast cells due to deletion. Comparison of single-cell gene expression between the placenta and the fetal brain further showed that specific genes such as plexin A1 ( ), phosphatase and actin regulator 1 ( ) and amyloid precursor-like protein 2 ( ) were differentially expressed between the EVT and STB cells of the placenta, and also, between the radial glia and ependymal cells of the fetal brain. Bulk RNA-seq analysis of the whole placenta and the fetal brain further identified genes differentially expressed in a similar manner between the placenta and the fetal brain due to the absence of . The deconvolution of reference cell types from the bulk RNA-seq data further showed that the loss of impacted the abundance of EVT cells relative to the stromal cells in the placenta, and that of the glia cells relative to the neuronal cells in the fetal brain. Together, the results of this study suggest that the ablation of causes deregulated gene expression in specific cell types of the placenta and the fetal brain in mice.