Neuronal Cadherin Research Articles

N-Cadherin — A Potential Target for Psychopharmacology

Glycoprotein N-cadherin (Neuronal cadherin) belongs to the family of calcium-dependent cell adhesion molecules, representing a key element that carries out intercellular contacts in brain neurons. However, it is involved not only in the mechanical connection of neurons, but also influences the specifics of the further development and functional state of the neuron. This is due to the active interaction of N-cadherin with many proteins at the pre- and post-synapse, initiating a cascade of reactions that provide such processes as long-term potentiation (underlying learning and memory), morphogenesis, neuronal recognition, activation of receptors (NMDA and AMPA types), regulation of cytoskeleton formation. This polyfunctionality is necessary for specific neurons to connect to each other in a certain way, and such adhesion leads to the coordination of cell behavior through intercellular signaling and spatio–temporal control of differential gene expression. Mutations in the genes responsible for the expression of N-cadherin lead to various disorders of the functional activity of the synapse and the processes of spatial orientation and memory. Thus, involvement in important neuroplastic processes regulating cognitive functions and behavior determines interest in studying the effect of drugs on N-cadherin. In particular, N-cadherin deserves closer consideration by pharmacologists as a potential target in the mechanism of action of various psychoactive substances.

Abstract 310: Cadherin-dependent modulation of chemosensitivity in oral tumor progression

Abstract The progression of healthy oral epithelia to an oral carcinoma often involves aberrant expression of a group of calcium-dependent transmembrane proteins called cadherins. Histological studies of human tumors have demonstrated increased expression of the epithelial-resident placental (P-cadherin) and ectopic expression of the mesenchymal neuronal (N-cadherin) cadherin in oral dysplasia. We hypothesized that these changes in cadherin expression during early oral tumor development could facilitate increases in survival signaling. We genetically modified dysplastic oral keratinocytes to overexpress P-cadherin or suppress endogenous expression of N-cadherin. P-cadherin overexpression and N-cadherin suppression independently elicited a 3-6-fold decrease in apoptosis levels in response to docetaxel treatment compared to similarly treated controls. We found that in untreated dysplastic cells, P- and N-cadherin expression had positive and negative correlations, respectively, with the activation of the survival-associated enzymes focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK), and AKT kinase. The total levels of nuclear factor kappa B (NFkb) were positively correlated with P-cadherin overexpression and reciprocally correlated with levels of N-cadherin. In docetaxel-treated dysplastic cells, we observed the reverse effect compared to untreated cells: the increased level of N-cadherin was positively correlated with FAK activity whereas FAK activity was suppressed by P-cadherin. P-cadherin expression in docetaxel-treated cells also increased activation of both MAPK and AKT, whereas alteration of N-cadherin levels had no effect. Because N-cadherin levels are known to increase in late-stage oral tumors, we extended these signaling studies to oral squamous carcinoma cells (OSCCs) expressing low or high levels of N-cadherin. In contrast to its suppression of survival pathways in docetaxel-treated dysplastic cells, in docetaxel-treated OSCCs, N-cadherin expression strongly enhanced phosphorylation of MAPK and AKT, and increased expression of NFkb. N-cadherin overexpression during this treatment also increased expression of the antiapoptotic proteins Mcl-1 and suppressed phosphorylation of the apoptotic regulator signal transducer and activator of transcription 3 (pSTAT3). Increase cadherin expression in all untreated cell lines increased expression of an inducer of epithelial to mesenchymal transition, the transmembrane protein mucin-1 (MUC1). N-cadherin overexpression also increased motility in both cell lines. Taken together, our data demonstrate antiapoptotic signaling directed by increased levels of P-cadherin in oral dysplasia and N-cadherin in OSCC, whereas increased levels of N-cadherin in dysplastic cells directed cellular signaling that were associated with a proapoptotic phenotype. Citation Format: Aaron Mody, Cassandra Decker, Kathryn R. Lawson. Cadherin-dependent modulation of chemosensitivity in oral tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 310.

The uPA/uPAR system in astrocytic wound healing.

The repair of injured tissue is a highly complex process that involves cell proliferation, differentiation, and migration. Cell migration requires the dismantling of intercellular contacts in the injured zone and their subsequent reconstitution in the wounded area. Urokinase-type plasminogen activator (uPA) is a serine proteinase found in multiple cell types including endothelial cells, smooth muscle cells, monocytes, and macrophages. A substantial body of experimental evidence with different cell types outside the central nervous system indicates that the binding of uPA to its receptor (uPAR) on the cell surface prompts cell migration by inducing plasmin-mediated degradation of the extracellular matrix. In contrast, although uPA and uPAR are abundantly found in astrocytes and uPA binding to uPAR triggers astrocytic activation, it is unknown if uPA also plays a role in astrocytic migration. Neuronal cadherin is a member of cell adhesion proteins pivotal for the formation of cell-cell contacts between astrocytes. More specifically, while the extracellular domain of neuronal cadherin interacts with the extracellular domain of neuronal cadherin in neighboring cells, its intracellular domain binds to β-catenin, which in turn links the complex to the actin cytoskeleton. Glycogen synthase kinase 3β is a serine-threonine kinase that prevents the cytoplasmic accumulation of β-catenin by inducing its phosphorylation at Ser33, Ser37, and Ser41, thus activating a sequence of events that lead to its proteasomal degradation. The data discussed in this perspective indicate that astrocytes release uPA following a mechanical injury, and that binding of this uPA to uPAR on the cell membrane induces the detachment of β-catenin from the intracellular domain of neuronal cadherin by triggering its extracellular signal-regulated kinase 1/2-mediated phosphorylation at Tyr650. Remarkably, this is followed by the cytoplasmic accumulation of β-catenin because uPA-induced extracellular signal-regulated kinase 1/2 activation also phosphorylates lipoprotein receptor-related protein 6 at Ser1490, which in turn, by recruiting glycogen synthase kinase 3β to its intracellular domain abrogates its effect on β-catenin. The cytoplasmic accumulation of β-catenin is followed by its nuclear translocation, where it induces the expression of uPAR, which is required for the migration of astrocytes from the injured edge into the wounded area.

RhoGEF Trio Regulates Radial Migration of Projection Neurons via Its Distinct Domains

The radial migration of cortical pyramidal neurons (PNs) during corticogenesis is necessary for establishing a multilayered cerebral cortex. Neuronal migration defects are considered a critical etiology of neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia, epilepsy, and intellectual disability (ID). TRIO is a high-risk candidate gene for ASDs and ID. However, its role in embryonic radial migration and the etiology of ASDs and ID are not fully understood. In this study, we found that the in vivo conditional knockout or in utero knockout of Trio in excitatory precursors in the neocortex caused aberrant polarity and halted the migration of late-born PNs. Further investigation of the underlying mechanism revealed that the interaction of the Trio N-terminal SH3 domain with Myosin X mediated the adherence of migrating neurons to radial glial fibers through regulating the membrane location of neuronal cadherin (N-cadherin). Also, independent or synergistic overexpression of RAC1 and RHOA showed different phenotypic recoveries of the abnormal neuronal migration by affecting the morphological transition and/or the glial fiber-dependent locomotion. Taken together, our findings clarify a novel mechanism of Trio in regulating N-cadherin cell surface expression via the interaction of Myosin X with its N-terminal SH3 domain. These results suggest the vital roles of the guanine nucleotide exchange factor 1 (GEF1) and GEF2 domains in regulating radial migration by activating their Rho GTPase effectors in both distinct and cooperative manners, which might be associated with the abnormal phenotypes in neurodevelopmental disorders.

Urokinase-type plasminogen activator promotes N-cadherin-mediated synaptic recovery in the ischemic brain

Urokinase-type plasminogen activator (uPA) is a serine proteinase that catalyzes the generation of plasmin on the cell surface and activates cell signaling pathways that promote remodeling and repair. Neuronal cadherin (NCAD) is a transmembrane protein that in the mature brain mediates the formation of synaptic contacts in the II/III and V cortical layers. Our studies show that uPA is preferentially found in the II/III and V cortical laminae of the gyrencephalic cortex of the non-human primate. Furthermore, we found that in murine cerebral cortical neurons and induced pluripotent stem cell (iPSC)-derived neurons prepared from healthy human donors, most of this uPA is associated with pre-synaptic vesicles. Our in vivo experiments revealed that in both, the gyrencephalic cortex of the non-human primate and the lissecephalic murine brain, cerebral ischemia decreases the number of intact synaptic contacts and the expression of uPA and NCAD in a band of tissue surrounding the necrotic core. Additionally, our in vitro data show that uPA induces the synthesis of NCAD in cerebral cortical neurons, and in line with these observations, intravenous treatment with recombinant uPA three hours after the onset of cerebral ischemia induces NCAD-mediated repair of synaptic contacts in the area surrounding the necrotic core.

CDH2/N-cadherin and early diagnosis of invasion in patients with ductal carcinoma in situ.

This proof-of-concept study investigates gene expression in core needle biopsies (CNB) to predict whether individuals diagnosed with ductal carcinoma in situ (DCIS) on CNB were affected by invasion at the time of diagnosis. Using a QuantiGene Plex 2.0 assay, 14 gene expression profiling was performed in 303 breast tissue samples. Preoperative diagnostic performance of a gene was measured by area under receiver-operating characteristic curve (AUC) with 95% confidence interval (CI). The gene mRNA positivity cutoff was computed using Gaussian mixture model (GMM); protein expression was measured by immunohistochemistry; DNA methylation was evaluated by targeted bisulfite sequencing. mRNA from 69% (34/49) mammoplasties, 72% (75/104) CNB DCIS, and 89% (133/150) invasive breast cancers (IBC) were analyzed. Based on pre-and post-surgery DCIS chart reviews, 21 cases were categorized as DCIS synchronous with invasion and 54 DCIS were pure DCIS without pathologic evidence of invasive disease. The ectopic expression of neuronal cadherin CDH2 was probable in 0% mammoplasties, 6% pure DCIS, 29% synchronous DCIS, and 26% IBC. The CDH2 mRNA positivity in preoperative biopsies showing pure DCIS was predictive of a final diagnosis of invasion (AUC = 0.67; 95% CI 0.53-0.80; P = 0.029). Site-specific methylation of the CDH2 promoter (AUC = 0.76; 95% CI 0.54-0.97; P = 0.04) and measurements of N-cadherin, a pro-invasive cell-cell adhesion receptor encoded by CDH2 (AUC = 0.8; 95% CI 0.66-0.99; P < 0.005) had a discriminating power allowing for discernment of CDH2-positive biopsy. Evidence of CDH2/N-cadherin expression, predictive of invasion synchronous with DCIS, may help to clarify a diagnosis and direct the course of therapy earlier in a patient's care.

Urokinase-Type Plasminogen Activator Protects Cerebral Cortical Neurons from Soluble Aβ-Induced Synaptic Damage.

Soluble amyloid β (Aβ)-induced synaptic dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that precedes the deposition of insoluble Aβ and correlates with the development of cognitive deficits better than the number of plaques. The mammalian plasminogen activation (PA) system catalyzes the generation of plasmin via two activators: tissue-type (tPA) and urokinase-type (uPA). A dysfunctional tPA-plasmin system causes defective proteolytic degradation of Aβ plaques in advanced stages of AD. In contrast, it is unknown whether uPA and its receptor (uPAR) contribute to the pathogenesis of this disease. Neuronal cadherin (NCAD) plays a pivotal role in the formation of synapses and dendritic branches, and Aβ decreases its expression in cerebral cortical neurons. Here we show that neuronal uPA protects the synapse from the harmful effects of soluble Aβ. However, Aβ-induced inactivation of the eukaryotic initiation factor 2α halts the transcription of uPA mRNA, leaving unopposed the deleterious effects of Aβ on the synapse. In line with these observations, the synaptic abundance of uPA, but not uPAR, is decreased in the frontal cortex of AD patients and 5xFAD mice, and in cerebral cortical neurons incubated with soluble Aβ. We found that uPA treatment increases the synaptic expression of NCAD by a uPAR-mediated plasmin-independent mechanism, and that uPA-induced formation of NCAD dimers protects the synapse from the harmful effects of soluble Aβ oligomers. These data indicate that Aβ-induced decrease in the synaptic abundance of uPA contributes to the development of synaptic damage in the early stages of AD.SIGNIFICANCE STATEMENT Soluble amyloid β (Aβ)-induced synaptic dysfunction is an early event in the pathogenesis of cognitive deficits in Alzheimer's disease (AD). We found that neuronal urokinase-type (uPA) protects the synapse from the deleterious effects of soluble Aβ. However, Aβ-induced inactivation of the eukaryotic initiation factor 2α decreases the synaptic abundance of uPA, leaving unopposed the harmful effects of Aβ on the synapse. In line with these observations, the synaptic expression of uPA is decreased in the frontal cortex of AD brains and 5xFAD mice, and uPA treatment abrogates the deleterious effects of Aβ on the synapse. These results unveil a novel mechanism of Aβ-induced synaptic dysfunction in AD patients, and indicate that recombinant uPA is a potential therapeutic strategy to protect the synapse before the development of irreversible brain damage.

Epithelial-to-mesenchymal transition in ameloblastoma: focus on morphologically evident mesenchymal phenotypic transition

The ameloblastoma is the most common and clinically significant odontogenic epithelial neoplasm known for its locally-invasive behaviour and high recurrence risk. Epithelial-to-mesenchymal transition (EMT) is a fundamental process whereby epithelial cells lose their epithelial characteristics and gain mesenchymal properties. EMT induction via transcription repression has been investigated in ameloblastoma. However, morphologically evident mesenchymal phenotypic transition remains ill-defined. To determine this, 24 unicystic (UA), 34 solid/multicystic (SA) and 18 recurrent ameloblastoma (RA) were immunohistochemically examined for three EMT-related mesenchymal markers, alpha smooth muscle actin (α-SMA), osteonectin and neuronal cadherin (N-cadherin). All three factors were heterogeneously detected in ameloblastoma samples (α-SMA, n=71/76, 93.4%; osteonectin, n=72/76, 94.7%; N-cadherin, n=24/76, 31.6%). In the tumoural parenchyma, immunoreactive cells were not morphologically distinct from their non-reactive cellular counterparts. Rather, α-SMA and osteonectin predominantly labelled the cytoplasm of central polyhedral > peripheral columnar/cuboidal tumour cells. N-cadherin demonstrated weak-to-moderate circumferential membranous staining in both neoplastic cell types and cytoplasmic expression in spindle-celled epithelium of desmoplastic amelobastoma. For all tumour subsets, α-SMA and osteonectin scored significantly higher in the stroma > parenchyma whilst α-SMA was overexpressed along the tumour invasive front > centre (p<0.05). Stromal N-cadherin scored higher in SA > UA and RA > UA (p<0.05). Other clinicopathological parameters showed no significant associations. Taken together, acquisition of mesenchymal traits without morphologically evident mesenchymal alteration suggests partial EMT in ameloblastoma. Stromal upregulation of these proteins in SA and RA implicates a role in local invasiveness.

Long non-coding RNA SUMO1P3 may promote cell proliferation, migration, and invasion of pancreatic cancer via EMT signaling pathway.

Long non-coding RNAs (lncRNAs) have been suggested to serve important roles in the development of a number of human cancer types. An increasing amount of data has indicated that the lncRNA small ubiquitin-like modifier 1 (SUMO1) pseudogene 3 (SUMO1P3) has been involved in various types of human cancer. However, the function SUMO1P3 in the development of pancreatic cancer remains unclear. Firstly, reverse transcription-quantitative polymerase chain reaction was performed to determine the expression of SUMO1P3 in pancreatic cancer tissues and cell lines. Then, cell counting kit-8, wound-healing and transwell assays were conducted to explore the effect of SUMO1P3 on pancreatic cancer cell proliferation, migration and invasion. Finally, the EMT-associated proteins were evaluated by western blotting. The results of the present study revealed that SUMO1P3 expression was elevated in pancreatic tissues compared with the corresponding adjacent normal tissues. Additionally, the data indicated that the increased expression of SUMO1P3 is significantly associated with tumor progression and the poor survival of patients with pancreatic cancer. Furthermore, the present study identified that SUMO1P3 knockdown may suppress the proliferation, migration and invasion of pancreatic cancer cells. Additionally, downregulation of SUMO1P3 suppressed the epithelial-mesenchymal transition (EMT) and increased the expression of epithelial cadherin, and decreased the expression of neuronal cadherin, vimentin and β-catenin. Taken together, the results of the present study demonstrated that SUMO1P3 may participate in EMT and pancreatic cancer progression, thus suggesting that it may be a novel diagnostic and therapeutic biological target for pancreatic cancer.

S100A6 promotes the proliferation and migration of cervical cancer cells via the PI3K/Akt signaling pathway.

Cervical cancer is the second most common gynecological cancer worldwide and remains one of the leading causes of cancer-associated mortality among women. S100A6 has been reported to be associated with the development of many types of cancer. The aim of the present study was to investigate the effect of S100A6 on the proliferation, apoptosis and migration of cervical cancer cells and its underlying molecular mechanisms. Quantative polymerase chain reaction (qPCR) was used to detect the basic mRNA level of S100A6 in HeLa, SiHa and CaSki cells. Western blot analysis was used to detect the protein level of S100A6, epithelial cadherin, neuronal cadherin, phosphorylated protein kinase B (p-Akt), t-Akt, p-glycogen synthase kinase 3β (GSK3β), t-GSK3β and β-catenin. Semi-qPCR was used to detect the mRNA level of Snail, Twist and Vimentin. MTT and Hoechst staining assays were used to detect the proliferation and apoptosis of cells, and wound healing and Transwell assays were used to detect the migration of cells. The results of the present study demonstrate that the levels of S100A6 were decreased in HeLa cells compared with in SiHa and CaSki cells. Overexpression of S100A6 in HeLa and CaSki cells promoted the proliferative and migratory ability, and had no significant effect on cellular apoptosis. Whereas the knockdown of S100A6 in SiHa and CaSki cells inhibited the proliferative and migratory ability, it had no significant effect on apoptosis. The overexpression of S100A6 in HeLa cells increased the levels of neuronal (N)-cadherin, vimentin, Snail and Twist. Conversely, knockdown of S100A6 in SiHa cells decreased the levels of N-cadherin, vimentin, Snail and Twist and increased the levels of epithelial (E)-cadherin. Furthermore, overexpression of S100A6 in HeLa cells activated the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, and treatment with the PI3K inhibitor LY294002 partially repressed S100A6-enhanced proliferation and migration of cervical cancer cells. These results indicate that S100A6 facilitates the malignant potential of cervical cancer cells, particularly metastatic ability and epithelial-mesenchymal transition, which is mediated by activating the PI3K/Akt signaling pathway.

Expression profile of N-cadherin and protocadherin-19 in postnatal mouse limbic structures.

Cadherins are a superfamily of calcium-dependent cell adhesion molecules that are involved in brain development and organization. Previous genetic studies revealed that mutations in protocadherin-19 (Pcdh19) lead to an epilepsy syndrome with a variable degree of cognitive disability. Seizure origins are located in the frontotemporal and limbic structures. Expression studies of Pcdh19 in mouse confirmed a widespread presence during brain development while the function and the pathogenesis of Pcdh19 are still unknown in mammals. The neuronal cadherin (N-cadherin; Ncdh) is known for its important role in neurulation, brain development and regulation of synaptic function. Studies in zebrafish revealed that both cadherins can interact with each other in cell adhesion. We investigated the expression pattern of Pcdh19 and Ncdh in limbic structures at four postnatal stages of C57BL/6J mice by using double-label in situ hybridization. Results confirm a strong expression of both, Ncdh and Pcdh19, in structures of the limbic system with overlapping expression patterns particularly within regions of the amygdala, the hippocampus and the ventral hypothalamus. A detailed analysis of the limbic system highlight clear expression boundaries between several nuclei and reveal the fine regulation of Pcdh19 and Ncdh expression during the first postnatal week. Most expression patterns of both cadherins remain constant with a few exceptions particularly between P2 and P5.

FoxM1 is associated with metastasis in colorectal cancer through induction of the epithelial-mesenchymal transition.

The aim of the present study was to investigate the role of forkhead box M1 (FoxM1) in epithelial-mesenchymal transition (EMT) and metastasis in colorectal cancer (CRC). Immunohistochemical assays were performed to detect FoxM1 and epithelial (E-) cadherin protein expression in 92 CRC, 61 colonic adenoma and 32 wild-type colonic tissue samples. Quantitative polymerase chain reaction (qPCR) assays were performed to determine the expression levels of FoxM1 and E-cadherin mRNAs in 30 CRC and adjacent normal mucosal tissues. RNA interference was used to knock down endogenous FoxM1 expression in CRC cell lines, and the migratory and invasive capacity of the CRC cells was analyzed. The expression of FoxM1, E-cadherin and neuronal (N-) cadherin in the CRC cell lines was evaluated using qPCR and Western blot analysis. The relative expression levels of FoxM1 mRNA and protein were significantly increased in the CRC tissues compared with those in the colonic adenoma and wild-type mucosal tissue samples (P<0.01). In contrast, the relative expression levels of E-cadherin mRNA and protein were significantly decreased in the CRC tissues compared with in the colonic adenoma and normal mucosal tissues (P<0.01). FoxM1 overexpression and decreased E-cadherin expression were significantly associated with poor colonic tissue differentiation, lymph node metastasis and an advanced tumor-node-metastasis stage. Additionally, the increased expression of FoxM1 was associated with a decrease in E-cadherin expression (P<0.01). Furthermore, RNA interference-mediated FoxM1 knockdown significantly inhibited the proliferation, migration and invasion of CRC cells. Downregulation of FoxM1 expression significantly increased E-cadherin expression and decreased N-cadherin expression. The results of the present study suggest that FoxM1 overexpression in tumor tissues is significantly associated with metastasis in CRC through the induction of EMT.

N-cadherin coordinates AMP kinase-mediated lung vascular repair.

Injury to the pulmonary circulation compromises endothelial barrier function and increases lung edema. Resolution of lung damage involves restoring barrier integrity, a process requiring reestablishment of endothelial cell-cell adhesions. However, mechanisms underlying repair in lung endothelium are poorly understood. In pulmonary microvascular endothelium, AMP kinase α1 (AMPKα1) stimulation enhances recovery of the endothelial barrier after LPS-induced vascular damage. AMPKα1 colocalizes to a discrete membrane compartment with the adhesion protein neuronal cadherin (N-cadherin). This study sought to determine N-cadherin's role in the repair process. Short-hairpin RNA against full-length N-cadherin or a C-terminally truncated N-cadherin, designed to disrupt the cadherin's interactions with intracellular proteins, were expressed in lung endothelium. Disruption of N-cadherin's intracellular domain caused translocation of AMPK away from the membrane and attenuated AMPK-mediated restoration of barrier function in LPS-treated endothelium. AMPK activity measurements indicated that lower basal AMPK activity in cells expressing the truncated N-cadherin compared with controls. Moreover, the AMPK stimulator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) failed to increase AMPK activity in cells expressing the modified N-cadherin, indicating uncoupling of a functional association between AMPK and the cadherin. Isolated lung studies confirmed a physiologic role for this pathway in vivo. AMPK activation reversed LPS-induced increase in permeability, whereas N-cadherin inhibition hindered AMPK-mediated repair. Thus N-cadherin coordinates the vascular protective actions of AMPK through a functional link with the kinase. This study provides insight into intrinsic repair mechanisms in the lung and supports AMPK stimulation as a modality for treating vascular disease.

Myosin X regulates neuronal radial migration through interacting with N-cadherin.

Proper brain function depends on correct neuronal migration during development, which is known to be regulated by cytoskeletal dynamics and cell-cell adhesion. Myosin X (Myo10), an uncharacteristic member of the myosin family, is an important regulator of cytoskeleton that modulates cell motilities in many different cellular contexts. We previously reported that Myo10 was required for neuronal migration in the developing cerebral cortex, but the underlying mechanism was still largely unknown. Here, we found that knockdown of Myo10 expression disturbed the adherence of migrating neurons to radial glial fibers through abolishing surface Neuronal cadherin (N-cadherin) expression, thereby impaired neuronal migration in the developmental cortex. Next, we found Myo10 interacted with N-cadherin cellular domain through its FERM domain. Furthermore, we found knockdown of Myo10 disrupted N-cadherin subcellular distribution and led to localization of N-cadherin into Golgi apparatus and endosomal sorting vesicle. Taking together, these results reveal a novel mechanism of Myo10 interacting with N-cadherin and regulating its cell-surface expression, which is required for neuronal adhesion and migration.

Polymorphisms within the neuronal cadherin (CDH2) gene are associated with obsessive-compulsive disorder (OCD) in a South African cohort.

OCD is characterised by recurrent obsessions and compulsions that result in severe distress and increased risk for comorbidity. Recently published findings have indicated that the neuronal cadherin gene (CDH2) plays a role in the development of canine OCD, and led us to investigate the human ortholog, CDH2, in a human OCD cohort. Seven CDH2 polymorphisms were selected and genotyped in a South African Caucasian cohort of 234 OCD patients and 180 healthy controls using TaqMan assays. Polymorphisms were analysed in a single-locus and haplotypic context. Of the seven polymorphisms, two reached statistical significance for OCD under additive and codominant models of inheritance (rs1120154 and rs12605662). CDH2 SNP, rs1120154, C-allele carriers were found to be significantly associated with lower risk to develop OCD compared to TT-homozygotes (OR = 0.49; 95% CI: 0.32-0.75; p < 0.001), and rs12605662 G-allele carriers were significantly associated with reduced risk OCD compared to TT-homozygotes (OR = 0.46; 95% CI: 0.30-0.71; p < 0.001), Furthermore, a single haplotype was found to infer an increased risk for OCD diagnosis (*rs8087457-rs1148374: A-T). Polymorphisms within the CDH2 gene are associated with susceptibility to OCD in a South African cohort.

The role of biological markers of epithelial to mesenchymal transition in oesophageal adenocarcinoma, an immunohistochemical study

BackgroundE-cadherin, β-catenin, epidermal growth factor receptor (EGFR), neuronal cadherin (N-cadherin) and Cyclin D1 are involved in epithelial to mesenchymal transition (EMT). However, the prognostic significance of EMT markers in oesophageal...

ShaoYao decoction ameliorates colitis-associated colorectal cancer by downregulating proinflammatory cytokines and promoting epithelial-mesenchymal transition.

sBackgroundShaoyao decoction (SYD) is a traditional Chinese medicine prescription formulated by Liu Wan-Su, a master of traditional Chinese medicine in Jin-Yuan Dynasty. SYD is effective in treating ulcerative colitis. Paeonol, a component of SYD, inhibits colorectal cancer (CRC) cell proliferation and induces CRC cell apoptosis. In this study, azoxymethane (AOM)/dextran sodium sulfate (DSS)–induced colitis-associated CRC (caCRC) model and CRC cell lines were used to examine the effects of SYD on CRC in vivo and in vitro.MethodsA translational medicine strategy based on phytomics quality control was adopted. Liquid chromatography was employed for the chemical characterization and chemical fingerprinting of SYD. Protein expression and macrophage existence were determined by immunohistochemistry and western blot. Serum cytokines were quantified by Luminex assay.ResultsAOM/DSS-induced caCRC phenotypically resembled human caCRC. SYD significantly increased the survival rate of the mice, ameliorated the general well-being of the mice, and reduced the incidence and multiplicity of colonic neoplasms. SYD inhibited epithelial–mesenchymal transition (EMT), as indicated by upregulated epithelia cadherin and downregulated neuronal cadherin, fibronectin, vimentin, and transcription factor Snail. SYD reduced the expression levels of serum interleukin 1β, interleukin-6, tumor necrosis factor α, tumor-associated macrophages, and p65. These results showed that SYD can attenuate proinflammatory cytokines and inhibit EMT.ConclusionsSYD ameliorates caCRC by suppressing inflammation and inhibiting EMT. SYD might be an alternative therapy for caCRC.

Cadherin switching during the formation and differentiation of the Drosophila mesoderm – implications for epithelial-to-mesenchymal transitions

ABSTRACT Epithelial-to-mesenchymal transition (EMT) is typically accompanied by downregulation of epithelial (E-) cadherin, and is often additionally accompanied by upregulation of a mesenchymal or neuronal (N-) cadherin. Snail represses transcription of the E-cadherin gene both during normal development and during tumour spreading. The formation of the mesodermal germ layer in Drosophila , considered a paradigm of a developmental EMT, is associated with Snail-mediated repression of E-cadherin and the upregulation of N-cadherin. By using genetic manipulation to remove or overexpress the cadherins, we show here that the complementarity of cadherin expression is not necessary for the segregation or the dispersal of the mesodermal germ layer in Drosophila . However, we discover different effects of E- and N-cadherin on the differentiation of subsets of mesodermal derivatives, which depend on Wingless signalling from the ectoderm, indicating differing abilities of E- and N-cadherin to bind to and sequester the common junctional and signalling effector β-catenin. These results suggest that the downregulation of E-cadherin in the mesoderm might be required to facilitate optimal levels of Wingless signalling.

Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder.

BackgroundObsessive-compulsive disorder (OCD), a severe mental disease manifested in time-consuming repetition of behaviors, affects 1 to 3% of the human population. While highly heritable, complex genetics has hampered attempts to elucidate OCD etiology. Dogs suffer from naturally occurring compulsive disorders that closely model human OCD, manifested as an excessive repetition of normal canine behaviors that only partially responds to drug therapy. The limited diversity within dog breeds makes identifying underlying genetic factors easier.ResultsWe use genome-wide association of 87 Doberman Pinscher cases and 63 controls to identify genomic loci associated with OCD and sequence these regions in 8 affected dogs from high-risk breeds and 8 breed-matched controls. We find 119 variants in evolutionarily conserved sites that are specific to dogs with OCD. These case-only variants are significantly more common in high OCD risk breeds compared to breeds with no known psychiatric problems. Four genes, all with synaptic function, have the most case-only variation: neuronal cadherin (CDH2), catenin alpha2 (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP). In the 2 Mb gene desert between the cadherin genes CDH2 and DSC3, we find two different variants found only in dogs with OCD that disrupt the same highly conserved regulatory element. These variants cause significant changes in gene expression in a human neuroblastoma cell line, likely due to disrupted transcription factor binding.ConclusionsThe limited genetic diversity of dog breeds facilitates identification of genes, functional variants and regulatory pathways underlying complex psychiatric disorders that are mechanistically similar in dogs and humans.

Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes

The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N=1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher's exact test P=0.014, OR=6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders.