X-linked protocadherin-19 mosaicism induces abnormal sorting of the olfactory nerve

Axon guidance is a fundamental process in the development of the olfactory sensory system. Although contact-dependent mechanisms regulate the guidance of olfactory sensory neuron (OSN) axons, it remains unclear how the X-linked mosaic expression of cell adhesion molecules affects axon coalescence into target glomeruli. In the present study, we focused on the cell–cell adhesion molecule protocadherin-19 (PCDH19). Mutations of the gene encoding this protein, which is located on the X chromosome, cause PCDH19-epilepsy in humans. In mice with HA-3×FLAG tag sequences knocked in at the 3′ end of the Pcdh19 gene, PCDH19 was localized to a part of OSN axons that extended towards the embryonic olfactory bulb (OB). Furthermore, PCDH19 was localized to glomeruli in postnatal developing and adult OBs. In Pcdh19 heterozygous female mice, the number of PCDH19-positive glomeruli was reduced, and in some glomeruli, PCDH19-positive and -negative axons were segregated, forming distinct compartments. This compartmentalized distribution of axons within individual glomeruli persisted into adulthood. Together, these results suggest that heterozygous Pcdh19 deletion alters the local sorting of olfactory sensory axons, resulting in their abnormal coalescence into glomeruli.