Gamma‐protocadherin localization at the synapse is associated with parameters of synaptic maturation

Abstract

Clustered protocadherins (Pcdhs) are a family of ~60 cadherin‐like proteins (divided into subclasses α, β, and γ) that regulate dendrite morphology and neural connectivity. Their expression is controlled through epigenetic regulation at a gene cluster encoding the molecules. During neural development, Pcdhs mediate dendrite self‐avoidance in some neuronal types through an uncharacterized anti‐adhesive mechanism. Pcdhs are also important for dendritic complexity in cortical neurons likely through a pro‐adhesive mechanism. Pcdhs have also been postulated to participate in synaptogenesis and connectivity. Some synaptic defects were noted in knockout animals, including synaptic number and physiology, but the role of these molecules in synaptic development is not understood. The effect of Pcdh knockout on dendritic patterning may present a confound to studying synaptogenesis. We showed previously that Pcdh‐γs are highly enriched in intracellular compartments in dendrites and spines with localization at only a few synaptic clefts. To gain insight into how Pcdh‐γs might affect synapses, we compared synapses that harbored Pcdh‐γs versus those that did not for parameters of synaptic maturation including pre‐ and postsynaptic size, postsynaptic perforations, and spine morphology by light microscopy in cultured hippocampal neurons and by serial section immuno‐electron microscopy in hippocampal CA1. In mature neurons, synapses immunopositive for Pcdh‐γs were larger in diameter with more frequent perforations. Analysis of spines in cultured neurons revealed that mushroom spines were more frequently immunopositive for Pcdh‐γs at their tips than thin spines. These results suggest that Pcdh‐γ function at the synapse may be related to promotion of synaptic maturation and stabilization.

γ-Protocadherins control synapse formation and peripheral branching of touch sensory neurons

“…Several lines of evidence have pointed to clustered protocadherins as potentially important molecular players in synapse development, function, or maintenance in the mammalian nervous system. Indeed, Pcdhgs are found at synaptic clefts and enriched in postsynaptic density (PSD) fractions of synaptosomes (Loh et al, 2016; Phillips et al, 2003; Wang et al, 2002b; Weiner et al, 2005) and their presence is associated with synapse maturation (LaMassa et al, 2021; Li et al, 2010; Phillips et al, 2003). Moreover, many synapse-associated molecules are found in Pcdhg protein complexes, including PSD-95, α-catenin, and neuroligin-1 (Han et al, 2010; Molumby et al, 2017), suggesting that Pcdhgs may directly control or modulate synapse assembly or composition.…”

Isoform requirement of clustered protocadherin for preventing neuronal apoptosis and neonatal lethality

“…Gene knockout studies targeting each of the three cPcdh clusters have shown that cPcdh plays a role in multiple aspects of recognition events, including axonal projection, dendritic self-avoidance, dendritic arbor complexity, and synapse formation. 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 Mice lacking all 58 isoforms ( Δαβγ mice) exhibit the most severe phenotype. They die immediately after birth due to massive neuronal death and synaptic loss in the brainstem and spinal cord.…”

Collective Mechanical Responses of Cadherin-Based Adhesive Junctions as Predicted by Simulations

“…The predicted mechanical strength of the PCDHγB4 trans dimers, isolated and in junctions, is intriguing given that the clustered PCDHs mainly play a role in neuronal recognition (82,83), while the adherens junction and the desmosome maintain epithelial cell-cell adhesion and must withstand significant mechanical stress. The γ-PCDHs, of which PCHDγB4 is a member, might play a role in adhesion at the synapse (98,144), but it is difficult to say if the clustered PCDHs are under or respond to any mechanical strain in vivo. Perhaps this brittle response is appropriate for more subtle types of mechanical stimuli that clustered PCDHs may experience in neurons during development, normal function, and in brain injury (66)(67)(68)(69)(70)(71)(72)(73)76).…”

“…However, axon growth and neuronal circuit formation during brain development is a dynamic process in which mechanical forces play a role (66), and forcegenerating and load-bearing proteins are also thought to regulate synapse development and function (67)(68)(69), while action potentials can cause neuronal deformation (70)(71)(72)(73)(74)(75), and traumatic brain injury can disrupt neuronal adhesion (76). Interestingly, the clustered protocadherin (PCDH) proteins, a subtype of cadherins expressed predominantly in the nervous system (77)(78)(79)(80)(81)(82)(83), form adhesive junctions (84)(85)(86)(87)(88)(89)(90) thought to signal for self-avoidance (91)(92)(93) and that may also be involved in synapse maturation and function (94)(95)(96)(97)(98). The clustered PCDH junctions may need to withstand mechanical stimuli, albeit in a different cellular and functional context than classical cadherins.…”