Non-clustered protocadherins (PCDHs) are calcium-dependent adhesion molecules which have attracted attention for their possible roles in the neuronal circuit formation during development and their implications in the neurological disorders such as autism and mental retardation. Previously, we found that a subset of the non-clustered PCDHs exhibited circuit-dependent expression patterns in thalamo-cortical connections in early postnatal rat brain, but such patterns disappeared in adulthood. In this study, we identified that the non-clustered PCDHs showed differential expression patterns along the septotemporal axis in the subregions of adult hippocampus and dentate gyrus with topographical preferences. The expressions of PCDH1, PCDH9, PCDH10 and PCDH20 showed septal preferences, whereas the expressions of PCDH8, PCDH11, PCDH17 and PCDH19 showed temporal preferences, suggesting that they play roles in the formation/maintenance of intrahippocampal circuits. PCDHs also exhibited the region-specific expression patterns in the areas connected to hippocampal formation such as entorhinal cortex, lateral septum, and basolateral amygdaloid complex. Furthermore, the expression levels of three PCDHs (PCDH8, PCDH19 and PCDH20) were regulated by the electroconvulsive shock stimulation of the brain in the adult hippocampus and dentate gyrus. These results suggest that non-clustered PCDHs are involved in the maintenance and plasticity of adult hippocampal circuitry.
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"An international GWAS meta-analysis including 8,696 epilepsy patients and 26,157 controls highlights PCDH7 as susceptibility gene for epilepsy in general and GGE syndromes in particular  . The PCHD7 gene encodes a calcium-dependent adhesion protein that is expressed in neurons of thalamocortical circuits and the hippocampus . PCDH7 has been implicated as neuronal target gene of MECP2  , the gene for Rett syndrome (OMIM #312750), which manifests as a progressive neurodevelopmental disorder with recurrent seizures. "
[Show abstract][Hide abstract]ABSTRACT: Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.
"Further investigation is therefore necessary in order to confirm whether the mechanisms disclosed using U251 cells also operate in growth cones. Embryonic brains express multiple d2-protocadherin subtypes, each of which is expressed by distinct neuronal populations (Hertel et al., 2008; Kim et al., 2007; Kim et al., 2010; Krishna et al., 2011). Because of their binding specificities, it is expected that each of the d2-protocadherins exclusively mediates the interactions between axons expressing the same d2-protocadherin subtype, and therefore serves to aid the sorting of axons that are derived from different groups of neurons. "
[Show abstract][Hide abstract]ABSTRACT: Protocadherins are a group of transmembrane proteins belonging to the cadherin superfamily that are subgrouped into 'clustered' and 'non-clustered' 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 self-avoidance. 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.
Full-text · Article · Mar 2015 · Journal of Cell Science
"Previous research has identified that non-clustered protocadherins (PCDHs) are groups of calcium-dependent adhesion proteins, expressing predominantly in the nervous system. PCDHs play significant roles in neuronal development such as neuronal migration and circuit formation (Yasuda et al., 2007), synaptic plasticity and implications in neurological disorders such as autism and mental retardation (Kim et al., 2010, 2011). In the present study, to comprehensively investigate the BCP-related expression of non-clustered PCDH family members in spinal cord, we examined the expression of all members of non-clustered PCDHs by RT-PCR. "
[Show abstract][Hide abstract]ABSTRACT: The majority of patients with metastatic bone disease experience moderate to severe pain. Bone cancer pain is usually progressive as the disease advances, and is very difficult to treat due to the poor understanding of the underlying mechanisms. Recent studies demonstrated that synaptic plasticity induces spinal cord sensitization and contributes to bone cancer pain. However, whether the synaptic plasticity is due to modifications of existing synapses or the formation of new synaptic connections is still unknown. Here we showed that a carcinoma implantation into a rats' tibia induced a significant increase in the number of excitability synapses in the dorsal horn, which contributes to the development of bone cancer pain. Previous studies identified that non-clustered protocadherins play significant roles in neuronal development and other implications in neurological disorders. In the present study, we showed that Protocadherin20 was significantly increased in the dorsal horn of cancer-bearing rats, while knockdown of Protocadherin20 with RNAi lentivirus reversed bone cancer-induced pain behaviors and decreased excitatory synaptogenesis in ipsilateral dorsal horn. In an in vitro study, we showed that knockdown of Protocadherin20 inhibited neurite outgrowth and excitatory synapse formation of dorsal neurons. These findings indicate that Protocadherin20 is required for the development of bone cancer pain probably by promoting the excitability synaptogenesis.
Full-text · Article · Aug 2013 · Neuropharmacology