The intracellular domain of the epilepsy protein PCDH19 regulates spine density in cortical neurons in vivo via Xlr genes.

It is believed that mosaic expression of PCDH19 leads to defective neuronal communication, but whether further roles beyond cell adhesion are critical for PCDH19 function in the cortex is currently unknown.

We confirm that the proteolytic processing of PCDH19, previously described in hippocampal neurons, also takes place in mouse cortical neurons in vivo and show that nuclear transport of its intracellular domain is mediated by importins. RNAseq analysis further indicates that the intracellular domain of PCDH19 leads to broad transcriptomic changes. Finally, we use in utero electroporation to provide the first in vivo data about the role of this cleaved intracellular domain in upper layer cortical neurons of male and female mice, where it reduces spine density through an increase in Xlr gene expression without affecting overall dendritic morphology.