Writing, Reading, and Translating the Clustered Protocadherin Cell Surface Recognition Code for Neural Circuit Assembly

Abstract

The ability of neurites of individual neurons to distinguish between themselves and neurites from other neurons and to avoid self (self-avoidance) plays a key role in neural circuit assembly in both invertebrates and vertebrates. Similarly, when individual neurons of the same type project into receptive fields of the brain, they must avoid each other to maximize target coverage (tiling). Counterintuitively, these processes are driven by highly specific homophilic interactions between cell surface proteins that lead to neurite repulsion rather than adhesion. Among these proteins in vertebrates are the clustered protocadherins (Pcdhs), and key to their function is the generation of enormous cell surface structural diversity. Here we review recent advances in understanding how a Pcdh cell surface code is generated by stochastic promoter choice; how this code is amplified and read by homophilic interactions between Pcdh complexes at the surface of neurons; and, finally, how the Pcdh code is translated to cellular function, which mediates self-avoidance and tiling and thus plays a central role in the development of complex neural circuits. Not surprisingly, Pcdh mutations that diminish homophilic interactions lead to wiring defects and abnormal behavior in mice, and sequence variants in the Pcdh gene cluster are associated with autism spectrum disorders in family-based genetic studies in humans.

The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death

“…In mice, the cPcdhs comprise a large family of 58 cadherin-related transmembrane molecules that are encoded by three tandemly-arranged gene clusters, Pcdh-alpha (Pcdha), Pcdh-beta (Pcdhb), and Pcdh-gamma (Pcdhg) (Wu and Maniatis, 1999). The cPcdhs are noted for their potential for immense cell surface diversity and selectivity to mediate complex neuronal interactions (Lefebvre, 2017;Mountoufaris et al, 2018). Consistent with this idea, cPcdhs play diverse roles in neurite patterning such as arborization, tiling, and self-avoidance which are proposed to result from homophilic cPcdh interactions that mediate adhesion, or self/non-self discrimination and repulsion Garrett et al, 2012;Ing-Esteves et al, 2018;Katori et al, 2009;Lefebvre et al, 2012;Molumby et al, 2016;Mountoufaris et al, 2017).…”

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

“…Interestingly, mutations found in de novo CNVs of FEZF2 allele-unlinked families underline the importance of synaptic networks as already reported (5,6,(33)(34)(35). In contrast, results from transmitted and de novo CNVs of FEZF2 allelelinked and unlinked families point to distinct gene classes with adhesion proteins involved in hemophilic interactions, such as clustered protocadherins (36,37), that are known to be involved in the establishment of the diversity of neural circuit assemblies and olfaction pathways. Links between olfaction and autism were recently found in ASD patients (38,39).…”

Tandem Directional CTCF Sites Balance Protocadherin Promoter Usage

“…Similar to the enormous diversity of DSCAM1 proteins in Drosophila, combinatorial cisand trans-interactions between mammalian clustered cell-surface protocadherin (Pcdh) proteins, encoded by the three closely-linked gene clusters (, , and ), endow individual neurons with a unique identity code and specific self-recognition module, which are required for neuronal migration, dendrite self-avoidance, and axon tiling in the brain [25][26][27][28][29][30][31]. The human Pcdh cluster contains 13 highly-similar, tandem-arrayed, unusually-large "alternate" variable exons (1-13) and 2 divergent "ubiquitous" variable exons (c1-c2), followed by 3 downstream small constant exons ( Figure 1A), reminiscent of the variable and constant genome organizations of immunoglobulin (Ig) and T-cell receptor (Tcr) clusters [25,32].…”