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Generalised morphological events of neurulation leading to neural tube closure. Transverse view. Neurulation begins in the flat neural plate, which generates lineages of the central nervous system. It is flanked on either side by the neural plate border and non-neural ectoderm. As neurulation progresses, the neural plate thickens, stratifies and begins to fold, while a ventral hinge point is formed at the notochord, a mesodermal tissue. The neural plate borders elevate, becoming the neural crest. As the neural tube fuses dorsally, neural crest cells migrate out of it, going on to form lineages of the peripheral nervous system. Closure of the nascent neural tube disconnects it from the overlying epidermis
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During early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two pr...
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The vertebrate hindbrain is segmented into rhombomeres (r) initially defined by distinct domains of gene expression. Previous studies have shown that noise-induced gene regulation and cell sorting are critical for the sharpening of rhombomere boundaries, which start out rough in the forming neural plate (NP) and sharpen over time. However, the mech...
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... Later on, the main enzyme will be switched to NSE, suggesting that the nervous cell is now a differentiated mature cell [21]. Also, the axons are negative to E-cadherin (a marker of pluripotent and undifferentiated neurons) further supporting the adult nature of the axons of RGC [22,23]. ...
The development of the optic nerve and its surrounding tissues during the early fetal period is a convoluted period because it spans both the organogenesis period and the fetal period. This study details the microscopic anatomy and histoembryology of the optic nerve in embryos during the early fetal period, including the second half of the first trimester of pregnancy. Serial sections through the orbit of variously aged embryos allowed us to analyze the nerve in both longitudinal and transverse aspects. A histological assessment and description of the structures surrounding and inside the nerve were performed, highlighting the cellular subtypes involved. By employing immunohistochemical techniques, we could characterize the presence and distribution of astrocytes within the optic nerve. Our findings suggest that by the 8th gestational week (WG) the structures are homologs to all the adult ones but with an early appearance so that maturation processes take place afterward. By this age, the axons forming the nerve are definitive adult axons. The glial cells do not yet exhibit adult phenotype, but their aspect becomes adult toward the 13th week. During its development the optic nerve increases in size then, at 14 weeks, it shrinks considerably, possibly through its neural maturation process. The morphological primordium of the blood–nerve barrier can be first noted at 10 WG and at 13 WG the morphological blood–nerve barrier is definitive. The meningeal primordium can be first noted as a layer of agglomerated fibroblasts, later toward 13 WG splitting in pachymeninx and leptomeninges and leaving space for intrinsic blood vessels.
... The effects of APOE3Ch on Wnt and Cadherin signaling uncovered by scRNA sequencing of cerebral organoids were unexpected and may operate via multiple mechanisms, ultimately resulting in β-catenin upregulation. Cadherins are a family of calciumdependent transmembrane adhesion proteins that link βand α-catenin to the actin cytoskeletal network (Punovuori et al., 2021) and also regulate cellular homeostasis through signaling mediating development, proliferation, apoptosis, and disease pathology (Yulis et al., 2018). Cadherins regulate calcium-dependent cell-cell adherent junctions, where the chelation of calcium abolishes adhesive activity and allows proteolytic degradation of cadherins (Nagar and Overduint, 1996;Kim et al., 2011). ...
A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) displayed extreme resistance to Alzheimer’s disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To further investigate the differences in biological processes attributed to APOE3Ch, we generated induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and a non-protected control, using CRISPR/Cas9 gene editing to modulate APOE3Ch expression. In the APOE3Ch cerebral organoids, we observed a protective pattern from early tau phosphorylation. ScRNA sequencing revealed regulation of Cadherin and Wnt signaling pathways by APOE3Ch, with immunostaining indicating elevated β-catenin protein levels. Further in vitro reporter assays unexpectedly demonstrated that ApoE3Ch functions as a Wnt3a signaling enhancer. This work uncovered a neomorphic molecular mechanism of protection of ApoE3 Christchurch, which may serve as the foundation for the future development of protected case-inspired therapeutics targeting AD and tauopathies.
... It has a critical role in tau aggregation [48]. Cadherin regulates complex signaling cascades including amyloid- protein precursor (APP), vascular endothelial growth factor (VEGF), morphogenesis, plasticity, Wnt-mediated signaling, etc., in neurodegenerative disorders [49]. These have important role for synaptic loss and decline in synaptic plasticity [50]. ...
Background:
Alzheimer's disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD.
Objective:
To investigate the potential therapeutic benefit of sildenafil on AD.
Methods:
We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil's mechanism-of-action.
Results:
We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32- 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49- 1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD.
Conclusions:
These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.
... Cadherins have a critical role in developing brain circuitry and mature synaptic function [56], hence genes encoding members of the cadherin superfamily play a vital role in the pathophysiology of neuropsychiatric illnesses. In the mammalian brain, the cadherin signaling system regulates adhesion molecules that are important in cell-cell contact [57]. The TGF-beta signaling pathway is crucial for the use-dependent control of GABAA synaptic transmission and dendritic homeostasis; moreover, a disruption in the excitatory-inhibitory balance in the hippocampal network may induce psychiatric-like behavior [58]. ...
Schizophrenia (SZ) is a chronic and devastating mental illness that affects around 20 million individuals worldwide. Cognitive deficits and structural and functional changes of the brain, abnormalities of brain ECM components, chronic neuroinflammation, and devastating clinical manifestation during SZ are likely etiological factors shown by affected individuals. However, the pathophysiological events associated with multiple regulatory pathways involved in the brain of this complex disorder are still unclear. This study aimed to develop a pipeline based on bioinformatics and systems biology approaches for identifying potential therapeutic targets involving possible biological mechanisms from SZ patients and healthy volunteers. About 420 overlapping differentially expressed genes (DEGs) from three RNA-seq datasets were identified. Gene ontology (GO), and pathways analysis showed several biological mechanisms enriched by the commonly shared DEGs, including extracellular matrix organization (ECM) organization, collagen fibril organization, integrin signaling pathway, inflammation mediated by chemokines and cytokines signaling pathway, and GABA-B receptor II and IL4 mediated signaling. Besides, 15 hub genes (FN1, COL1A1, COL3A1, COL1A2, COL5A1, COL2A1, COL6A2, COL6A3, MMP2, THBS1, DCN, LUM, HLA-A, HLA-C, and FBN1) were discovered by comprehensive analysis, which was mainly involved in the ECM organization and inflammatory signaling pathway. Furthermore, the miRNA target of the hub genes was analyzed with the random-forest-based approach software miRTarBase. In addition, the transcriptional factors and protein kinases regulating overlapping DEGs in SZ, namely, SUZ12, EZH2, TRIM28, TP53, EGR1, CSNK2A1, GSK3B, CDK1, and MAPK14, were also identified. The results point to a new understanding that the hub genes (fibronectin 1, collagen, matrix metalloproteinase-2, and lumican) in the ECM organization and inflammatory signaling pathways may be involved in the SZ occurrence and pathogenesis.
... There are many different classes of cadherins including E-cadherins, placental cadherins (P-cadherins), neural cadherins (N-cadherins) and liver cell adhesion molecule (L-CAM) [25]. E-cadherin is essential for the maintenance of epithelial integrity and plays important role in the formation of tissues during gastrulation, neurulation and organogenesis [25][26][27][28]. E-cadherin is connected with the cytoskeleton through β-catenin and maintains cellcell adhesion. ...
Introduction:
In this study we analyzed CD105 (endoglin) and E-cadherin expression in laryngeal squamous cell carcinoma (LSCC) to evaluate their clinicopathologic significance.
Material and methods:
Expression of CD105 and E-cadherin was examined immunohistochemically using paraffin-embedded archival tissues of 72 (35 glottic and 37 supraglottic) previously untreated LSCC male patients. The mean value of the positively-stained microvessels for CD105 counted in four hot spots for each case was used as the final intratumoralmicrovessel density (MVD). A staining score of E-cadherin was calculated based on the percentage of cells stained (0-100%).
Results:
MVD was significantly higher in patients with advanced TNM stage (P = 0.004) and younger than 65 (P = 0.008). Nodal metastases were more frequent in the cases with low E-cadherin expression (P = 0.000). Tumor recurrence was associated with advanced TNM stage (P = 0.035) and high MVD (P = 0.002). A high MVD was an independent predictor of malignancy recurrence (P = 0.021). The log-rank test showed a significant difference in the disease-free interval in patients stratified according to the MVD value (P = 0.016). Spearman's rank correlation test did not show a significant correlation between E-cadherin and CD105 expression.
Conclusions:
CD105-assessed MVD and expression of E-cadherin are promising prognostic factors for the outcome of patients with LSCC. Increased expression of CD105 could help predict patients with an increased risk of developing loco-regional recurrence after surgical treatment. Decreased E-cadherin expression is a potential predictor of lymph node metastases.
... The development of ap1g1 +/− heterozygous embryos till adult age, indicates that ap1g1 expression levels suffice to permit cadherin-mediated AJ functions. However, cadherins have functions in signal transduction pathways, which are independent of their functions in AJ and one can speculate that those activities may not suffice for proper tissue development [47]. AJ are metastable and are continuously disassembled and reorganized. ...
In vertebrates, two homologous heterotetrameric AP1 complexes regulate the intracellular protein sorting via vesicles. AP-1 complexes are ubiquitously expressed and are composed of four different subunits: γ, β1, μ1 and σ1. Two different complexes are present in eukaryotic cells, AP1G1 (contains γ1 subunit) and AP1G2 (contains γ2 subunit); both are indispensable for development. One additional tissue-specific isoform exists for μ1A, the polarized epithelial cells specific to μ1B; two additional tissue-specific isoforms exist for σ1A: σ1B and σ1C. Both AP1 complexes fulfil specific functions at the trans-Golgi network and endosomes. The use of different animal models demonstrated their crucial role in the development of multicellular organisms and the specification of neuronal and epithelial cells. Ap1g1 (γ1) knockout mice cease development at the blastocyst stage, while Ap1m1 (μ1A) knockouts cease during mid-organogenesis. A growing number of human diseases have been associated with mutations in genes encoding for the subunits of adaptor protein complexes. Recently, a new class of neurocutaneous and neurometabolic disorders affecting intracellular vesicular traffic have been referred to as adaptinopathies. To better understand the functional role of AP1G1 in adaptinopathies, we generated a zebrafish ap1g1 knockout using CRISPR/Cas9 genome editing. Zebrafish ap1g1 knockout embryos cease their development at the blastula stage. Interestingly, heterozygous females and males have reduced fertility and showed morphological alterations in the brain, gonads and intestinal epithelium. An analysis of mRNA profiles of different marker proteins and altered tissue morphologies revealed dysregulated cadherin-mediated cell adhesion. These data demonstrate that the zebrafish model organism enables us to study the molecular details of adaptinopathies and thus also develop treatment strategies.
... The effects of APOE3Ch on Wnt and Cadherin signaling uncovered by scRNA-sequencing of cerebral organoids were unexpected and may operate via multiple mechanisms ultimately resulting in β-catenin upregulation. Cadherins are a family of calcium dependent transmembrane adhesion proteins that link β and α catenin to the actin cytoskeletal network (Punovuori, Malaguti, and Lowell 2021) and also regulate cellular homeostasis through signaling mediating development, proliferation, apoptosis, and disease pathology (Yulis, Kusters, and Nusrat 2018). Cadherins regulate calcium dependent cell-cell adherent junctions, where the chelation of calcium abolishes adhesive activity and allows proteolytic degradation of cadherins (Nagar and Overduint 1996;Kim et al. 2011). ...
Alzheimer′s disease (AD) is the most common cause of dementia among older adults. APOE3 Christchurch (R136S, APOE3Ch) variant homozygosity was reported in an individual with extreme resistance to autosomal dominant AD due to the PSEN1 E280A mutation. This subject had a delayed clinical age at onset and resistance to tauopathy and neurodegeneration despite extremely high amyloid plaque burden. We established induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and from a non-protected kindred control (with PSEN1 E280A and APOE3/3). We used CRISPR/Cas9 gene editing to successfully remove the APOE3Ch to wild type in iPS cells from the protected case and to introduce the APOE3Ch as homozygote in iPS cells from the non-protected case to examine causality. We found significant reduction of tau phosphorylation (pTau 202/205 and pTau396) in cerebral organoids with the APOE3Ch variant, consistent with the strikingly reduced tau pathology found in the resistant case. We identified Cadherin and Wnt pathways as signaling mechanisms regulated by the APOE3Ch variant through single cell RNA sequencing in cerebral organoids. We also identified elevated β-catenin protein, a regulator of tau phosphorylation, as a candidate mediator of APOE3Ch resistance to tauopathy. Our findings show that APOE3Ch is necessary and sufficient to confer resistance to tauopathy in an experimental ex-vivo model establishing a foundation for the development of novel, protected case-inspired therapeutics for tauopathies, including Alzheimer′s.
... Taken together, these results suggest that cardiac crest from Ets1 KO mutants have increased cell-cell adhesion compared to controls. N-cadherin plays a crucial role in NC migration (20,21) and previous studies have demonstrated that N-cadherin over-expression in the chick blocked their migration (20,21). We hypothesized that the cell migration defect observed in vivo may result from impaired expression of N-cadherin. ...
... Taken together, these results suggest that cardiac crest from Ets1 KO mutants have increased cell-cell adhesion compared to controls. N-cadherin plays a crucial role in NC migration (20,21) and previous studies have demonstrated that N-cadherin over-expression in the chick blocked their migration (20,21). We hypothesized that the cell migration defect observed in vivo may result from impaired expression of N-cadherin. ...
Ets1 deletion in some mouse strains causes septal defects and has been implicated in human congenital heart defects in Jacobsen syndrome, in which one copy of the Ets1 gene is missing. Here, we demonstrate that loss of Ets1 in mice results in a decrease in neural crest cells migrating into the proximal outflow tract cushions during early heart development, with subsequent malalignment of the cushions relative to the muscular ventricular septum, resembling double outlet right ventricle (DORV) defects in humans. Consistent with this, we find that cultured cardiac neural crest cells from Ets1 mutant mice or derived from iPS cells from Jacobsen patients exhibit decreased migration speed and impaired cell-to-cell interactions. Together, our studies demonstrate a critical role for ETS1 for cell migration in cardiac neural crest cells that are required for proper formation of the proximal outflow tracts. These data provide further insights into the molecular and cellular basis for development of the outflow tracts, and how perturbation of neural crest cells can lead to DORV.
... Particularly, a protocadherin fat 4 and a secreted neural cadherin protein with transmembrane domains were found in the chiton shell matrix. Both molecules are predominantly expressed in the nervous system and have a close relationship with neural development in vertebrate animals (Morishita and Yagi 2007;Punovuori et al. 2021). Domain analysis indicated the combination of cadherin domains with other extracellular domains such as fibronectin type III, Laminin G, and EGF. ...
The first step for animals to interact with external environment is to sense. Unlike vertebrate animals with flexibility, it is challenging for ancient animals that are less flexible especially for mollusca with heavy shells. Chiton, as an example, has eight overlapping shells covering almost the whole body, is known to incorporate sensory units called aesthetes inside the shell. We used micro-computed tomography combined with quantitative image analysis to reveal the optimized shell geometry to resist force and the aesthetes’ global distribution at the whole animal levels to facilitate sense from diverse directions both in the seawater and air. Additionally, shell proteomics combined with transcriptome reveals shell matrix proteins responsible for shell construction and potentially sensory function, highlighting unique cadherin-related proteins among mollusca. Together, this multi-level evidence of sensory units in the chiton shell may shed light on the formation of chiton shells and inspire the design of hard armor with sensory function.
... N-cadherin plays an important role in maintaining the structural integrity of the neural tube and cortical structure during development (Radice et al., 1997;Kadowaki et al., 2007;Punovuori et al., 2021). The complexity of the CNS depends on key role played by N-cadherin, which controls cell migration, synapse formation and maintenance of progenitor pool (Togashi et al., 2002;Bekirov et al., 2008;Rieger et al., 2009;Camand et al., 2012;de Agustín-Durán et al., 2021). ...
Alcohol exposure during pregnancy disrupts the development of the brain and produces long lasting behavioral and cognitive impairments collectively known as Fetal Alcohol Spectrum Disorders (FASDs). FASDs are characterized by alterations in learning, working memory, social behavior and executive function. A large body of literature using preclinical prenatal alcohol exposure models reports alcohol-induced changes in architecture and activity in specific brain regions affecting cognition. While multiple putative mechanisms of alcohol’s long-lasting effects on morphology and behavior have been investigated, an area that has received less attention is the effect of alcohol on cell adhesion molecules (CAMs). The embryo/fetal development represents a crucial period for Central Nervous System (CNS) development during which the cell-cell interaction plays an important role. CAMs play a critical role in neuronal migration and differentiation, synaptic organization and function which may be disrupted by alcohol. In this review, we summarize the physiological structure and role of CAMs involved in brain development, review the current literature on prenatal alcohol exposure effects on CAM function in different experimental models and pinpoint areas needed for future study to better understand how CAMs may mediate the morphological, sensory and behavioral outcomes in FASDs.
