Protocadherins branch out: Multiple roles in dendrite development

Abstract

The proper formation of dendritic arbors is a critical step in neural circuit formation, and as such defects in arborization are associated with a variety of neurodevelopmental disorders. Among the best gene candidates are those encoding cell adhesion molecules, including members of the diverse cadherin superfamily characterized by distinctive, repeated adhesive domains in their extracellular regions. Protocadherins (Pcdhs) make up the largest group within this superfamily, encompassing over 80 genes, including the ∼60 genes of the α-, β-, and γ-Pcdh gene clusters and the non-clustered δ-Pcdh genes. An additional group includes the atypical cadherin genes encoding the giant Fat and Dachsous proteins and the 7-transmembrane cadherins. In this review we highlight the many roles that Pcdhs and atypical cadherins have been demonstrated to play in dendritogenesis, dendrite arborization, and dendritic spine regulation. Together, the published studies we discuss implicate these members of the cadherin superfamily as key regulators of dendrite development and function, and as potential therapeutic targets for future interventions in neurodevelopmental disorders.

Regulation of neural circuit formation by protocadherins

“…Given the important functions the γ-Pcdhs play in proper dendrite formation [18,35,54-56,82,95-97,102,104,105], it is perhaps not surprising that they have been implicated in Down syndrome (DS) and Fetal alcohol spectrum disorders (FASDs). Both of these neurodevelopmental disorders are characterized by defective dendritic arborization, abnormal synaptic formation, and disrupted dendritic spine morphology [163-165].…”

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

“…Protocadherins are highly expressed in the nervous system and localize to synapses. Based on their spatial and temporal expression pattern in the brain and on recent reports, protocadherins have roles in dendritic development and synaptic connections (Hirano et al, 1999; Frank and Kemler, 2002; Kim et al, 2007, 2011b; Keeler et al, 2015). For example, PCDH10 expression is regulated by neuronal activity and its function is crucial for forebrain axon outgrowth and the proper patterning of thalamocorticial projections (Uemura et al, 2007; Morrow et al, 2008).…”

Regulation of Wnt signaling by protocadherins

“…Individual non-clustered δ-Pcdhs are expressed by discrete neuronal subsets throughout the brain, and functional studies collectively have revealed roles in axon outgrowth and pathfinding, synaptic plasticity, and synapse elimination [84, 86, 110, 155–163]. Though not the focus of this review, the many roles of Pcdhs in the nervous system have been discussed extensively in several recent reviews ([1, 2, 164–166]; from this special issue, see Light and Jontes, 2017; El Hajj et al, [132]; Aviles and Lefebvre, [79], Rubinstein et al, 2017; Phillips et al, [167]; Hirayama and Yagi, [120]).…”

“…Functional studies have implicated numerous Pcdhs in the regulation of neuronal survival, axon outgrowth and targeting, dendrite arbor complexity, the self-avoidance of sister axon and dendrite branches, and synaptogenesis. Several Pcdh genes also have been implicated, either by mutation or epigenetic dysregulation, in a wide variety of neurological and neurodevelopmental disorders, including epilepsy, mood disorders, autism, and schizophrenia (see reviews by Peek, et al [1] and Keeler et al [2], as well as the other reviews in this special issue).…”