Emerging roles of protocadherins: from self-avoidance to enhancement of motility

Abstract

Protocadherins are a group of transmembrane proteins belonging to the cadherin superfamily that are subgrouped into 'clustered' and 'nonclustered' protocadherins. Although cadherin superfamily members are known to regulate various forms of cell-cell interactions, including cell-cell adhesion, the functions of protocadherins have long been elusive. Recent studies are, however, uncovering their unique roles. The clustered protocadherins regulate neuronal survival, as well as dendrite self-avoidance. Combinatorial expression of clustered protocadherin isoforms creates a great diversity of adhesive specificity for cells, and this process is likely to underlie the dendritic selfavoidance. Non-clustered protocadherins promote cell motility rather than the stabilization of cell adhesion, unlike the classic cadherins, and mediate dynamic cellular processes, such as growth cone migration. Protocadherin dysfunction in humans is implicated in neurological disorders, such as epilepsy and mental retardation. This Commentary provides an overview of recent findings regarding protocadherin functions, as well as a discussion of the molecular basis underlying these functions.

PTEN deletion increases hippocampal granule cell excitability in male and female mice

“…PTEN is a known regulator of dendritic growth (Chow et al, 2009), and protocadherins are implicated in regulating dendrite self-avoidance (Hayashi and Takeichi, 2015). The specific molecules that regulate dendrite self-avoidance in granule cells, however, have yet to be elucidated.…”

The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders

“…In any case, the critical developmental role for such molecules depends upon their ability to mediate homo-or heterophilic interactions. For example, in the earliest developmental stages, strong homophilic calciumdependent cell interactions involving the function of Cadherin family components contribute to the control of events of key ontogenetic relevance such as germ layer separation (Stepniak et al, 2009;Hirano and Takeichi, 2012;McKeown et al, 2013;Barriga and Mayor, 2015;Hayashi and Takeichi, 2015;Duband et al, 2015). However, it is also worth mentioning that members of the same family may mediate the control of later developmental events as neurite growth (Gartner et al, 2012;Hayashi et al, 2014;Stoeckli, 2014).…”

Antiparallel protocadherin homodimers use distinct affinity- and specificity-mediating regions in cadherin repeats 1-4

“…Clustered Pcdhs thus function analogously to insect Dscam isoforms to mediate neuronal identity (Zipursky and Sanes, 2010). Clustered Pcdhs are also broadly involved in synapse formation and maintenance, neuronal connectivity and neuronal survival (Hayashi and Takeichi, 2015; Keeler et al, 2015). Non-clustered Pcdhs play key roles in neuronal development (Keeler et al, 2015; Kim et al, 2011).…”