Kcnj2 regulates electrical activity-induced gene networks in embryonic mouse palate shelves

Cleft palate interferes with eating, drinking, breathing, and speech, causing significant human suffering. Fetal exposure to many medications that target ion channels increases the incidence of cleft palate. Cleft palate could be prevented by understanding how ion channels contribute to palatal development. Ion channels regulate the electrical properties of cells. We discovered that the mouse embryonic palate mesenchymal cells are electrically active, like neurons. In neurons, electrical activity regulates transcription cell-autonomously and regulates the secretion of chemical cues. We discovered that electrical activity regulates secretion of bone morphogenetic protein (BMP4) from mouse palate mesenchymal cells. The next important step is to determine how electrical activity affects transcription to control palate development. Loss of a potassium channel called Kcnj2 (Kcnj2^KO/KO) alters electrical activity in palate mesenchyme cells and causes cleft palate in mice. We compared single cell RNA sequencing datasets from Kcnj2^KO/KO and wildtype E13.5 mouse anterior palate shelves to define how electrical activity affects gene expression cell autonomously and in surrounding cells. Our data reveal that Kcnj2^KO/KO alters a network of calcium-induced transcription factors and downstream effectors. These data also reveal that loss of Kcnj2 affects gene expression outside of the cells that express Kcnj2 consistent with disruption of BMP signaling.