Delta-protocadherins in health and disease

The protocadherin family comprises clustered and nonclustered protocadherin genes. The nonclustered genes encode mainly δ-protocadherins, which deviate markedly from classical cadherins. They can be subdivided phylogenetically into δ0-protocadherins (protocadherin-20), δ1-protocadherins (protocadherin-1, -7, -9, and -11X/Y), and δ2-protocadherins (protocadherin-8, -10, -17, -18, and -19). δ-Protocadherins share a similar gene structure and are expressed as multiple alternative splice forms differing mostly in their cytoplasmic domains (CDs). Some δ-protocadherins reportedly show cell-cell adhesion properties. Individual δ-protocadherins appear to be involved in specific signaling pathways, as they interact with proteins such as TAF1/Set, TAO2β, Nap1, and the Frizzled-7 receptor. The spatiotemporally restricted expression of δ-protocadherins in various tissues and species and their functional analysis suggest that they play multiple, tightly regulated roles in vertebrate development. Furthermore, several δ-protocadherins have been implicated in neurological disorders and in cancers, highlighting the importance of scrutinizing their properties and their dysregulation in various pathologies.