Localization of nectin-2δ at perivascular astrocytic endfoot processes and degeneration of astrocytes and neurons in nectin-2 knockout mouse brain

• Nectin-2δ was expressed mainly in astrocytes.
• Nectin-2δ was localized at adhesion sites between cultured astrocytes.
• Nectin-2δ was localized on the plasma membrane of astrocytic perivascular endfeet.
• Genetic ablation of nectin-2 caused degeneration of astrocytes and neurons.

Nectins are Ca2+-independent immunoglobulin-like cell–cell adhesion molecules. In the nervous system, among four members (nectin-1, -2, -3, and -4), nectin-1 and -3 are asymmetrically localized at puncta adherentia junctions formed between the mossy fiber terminals and the dendrites of CA3 pyramidal neurons in the mouse hippocampus and heterophilic trans-interactions between nectin-1 and nectin-3 are involved in the selective interaction of axons and dendrites of cultured neurons. By contrast, nectin-2, which has two splicing variants, nectin-2α and -2δ, has not been well characterized in the brain. We showed here that nectin-2α was expressed in both cultured mouse neurons and astrocytes whereas nectin-2δ was selectively expressed in the astrocytes. Nectin-2δ was localized at the adhesion sites between adjacent cultured astrocytes, but in the brain it was localized on the plasma membranes of astrocytic perivascular endfoot processes facing the basement membrane of blood vessels. Genetic ablation of nectin-2 caused degeneration of astrocytic perivascular endfoot processes and neurons in the cerebral cortex. These results uncovered for the first time the localization and critical functions of nectin-2 in the brain.