Regulation of neural circuit formation by protocadherins

Abstract

The protocadherins (Pcdhs), which make up the most diverse group within the cadherin superfamily, were first discovered in the early 1990s. Data implicating the Pcdhs, including ~60 proteins encoded by the tandem Pcdha, Pcdhb, and Pcdhg gene clusters and another ~10 non-clustered Pcdhs, in the regulation of neural development have continually accumulated, with a significant expansion of the field over the past decade. Here, we review the many roles played by clustered and non-clustered Pcdhs in multiple steps important for the formation and function of neural circuits, including dendrite arborization, axon outgrowth and targeting, synaptogenesis, and synapse elimination. We further discuss studies implicating mutation or epigenetic dysregulation of Pcdh genes in a variety of human neurodevelopmental and neurological disorders. With recent structural modeling of Pcdh proteins, the prospects for uncovering molecular mechanisms of Pcdh extracellular and intracellular interactions, and their role in normal and disrupted neural circuit formation, are bright.

Keywords: Axon outgrowth; Axonal targeting; Cell adhesion molecules; Dendrites; Dendritic arborization; Disease; Synapse elimination; Synaptogenesis.

Fig. 1

The protocadherin gene clusters. a Schematic of the murine Pcdha, Pcdhb, and Pcdhg gene clusters on chromosome 18. A very similar structure is observed for the human clusters at chromosome 5q31. b The exon structure of the Pcdhg cluster is expanded below, with an example of the transcription initiation and splicing pattern (for B2, in this instance). c Schematic of the Pcdhg spliced transcripts generated by the cluster; each mature transcript consists of one large variable exon (yellow, green, or purple) and the three small constant exons (black). d Protein structure of the γ-Pcdhs (α-Pcdhs are identical in structure; β-Pcdhs lack any constant domain). Six extracellular cadherin (EC) repeats, a transmembrane domain, and a variable cytoplasmic domain are encoded by each variable exon; the constant exons encode a 125 amino acid C-terminal domain. Ovals indicate the sites of “cluster control regions”, enhancers required for normal expression patterns of the Pcdh clusters

Fig. 2

Domain structures of clustered and non-clustered protocadherins. Schematic of the protein domains found in α-, β-, and γ-Pcdhs, with known roles of each domain indicated. EC1 is required for efficient surface expression (and therefore homophilic interaction) of clustered Pcdhs. EC2 and EC3 determine the specificity of antiparallel homophilic binding, which also involves contacts between EC1 and EC4. This antiparallel trans-interaction of opposed EC1–4 domains has also been shown to occur for the δ2-Pcdhs. EC6 of the γ-Pcdhs is required for interaction with α-Pcdhs for their efficient delivery to the cell surface. The variable cytoplasmic domain is involved in γ-Pcdh intracellular trafficking and their regulation of Wnt signaling, while a serine at the lipid-binding C-terminus of the constant domain is a target for PKC phosphorylation. The cytoplasmic domains of δ1- and δ2-Pcdhs harbor conserved domains (CM1–3) that may bind several intracellular signaling proteins, including PP1α. The δ2-Pcdhs (and the δ1-Pcdh Pcdh9) also harbor a wave interacting receptor sequence (WIRS) motif that mediates interaction with the WAVE complex