Functional roles of p120ctn family of proteins in central neurons

Li, Yuan; Arikkath, Jyothi

doi:10.1016/j.semcdb.2017.05.027

Cited by 20 publications

(29 citation statements)

References 118 publications

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“…Proteins affected by CYP46A1 activation and Cyp46a1 ablation were also different, except CTNND2, DPYSL2, GAP43, MAP1B, MAP6, MARCKS, PKP4, and SAMD14 ( Fig. 6B), which all pertain to neurite growth excluding SAMD14 (122)(123)(124)(125)(126)(127).…”

Section: Brain Phosphoproteomementioning

confidence: 99%

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

Petrov

Mast

et al. 2019

FASEB j.

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Efavirenz (EFV) is an anti‐HIV drug, and cytochrome P450 46A1 (CYP46A1) is the major brain cholesterol hydroxylase. Previously, we discovered that EFV activates CYP46A1 and improves behavioral performance in 5XFAD mice, an Alzheimer's disease model. Herein, the unbiased omics and other approaches were used to study 5XFAD mice in the amyloid‐decreasing paradigm of CYP46A1 activation by EFV. These approaches revealed increases in the brain levels of postsynaptic density protein 95, gephyrin, synaptophysin, synapsin, glial fibrillary acidic protein, and CYP46A1 and documented altered expression and phosphorylation of 66 genes and 77 proteins, respectively. The data obtained pointed to EFV effects at the synaptic level, plasmin‐depended amyloid clearance, inflammation and microglia phenotype, oxidative stress and cellular hypoxia, autophagy and ubiquitin‐proteasome systems as well as apoptosis. These effects could be realized in part via changes in the Ca2+‐, small GTPase, and catenin signaling. A model is proposed, in which CYP46A1‐dependent lipid raft rearrangement and subsequent decrease of protein phosphorylation are central in EFV effects and explain behavioral improvements in EFV‐treated 5XFAD mice.—Petrov, A. M., Mast, N., Li, Y., Pikuleva, I. A. The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment. FASEB J. 33, 8782–8798 (2019). http://www.fasebj.org

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Section: Brain Phosphoproteomementioning

confidence: 99%

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

Petrov

Mast

et al. 2019

FASEB j.

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“…The armadillo family member p120ctn has many functions in cells [18,48,49], but its role in vivo remains largely unaddressed. Using a full p120ctn knock-out approach, we found that up to the early stage of gastrulation, mouse development occurs normally in the absence of p120ctn [29].…”

Section: Discussionmentioning

confidence: 99%

Neural defects caused by total and Wnt1-Cre mediated ablation of p120ctn in mice

et al. 2020

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Background: p120 catenin (p120ctn) is an important component in the cadherin-catenin cell adhesion complex because it stabilizes cadherin-mediated intercellular junctions. Outside these junctions, p120ctn is actively involved in the regulation of small GTPases of the Rho family, in actomyosin dynamics and in transcription regulation. We and others reported that loss of p120ctn in mouse embryos results in an embryonic lethal phenotype, but the exact developmental role of p120ctn during brain formation has not been reported. Results: We combined floxed p120ctn mice with Del-Cre or Wnt1-Cre mice to deplete p120ctn from either all cells or specific brain and neural crest cells. Complete loss of p120ctn in mid-gestation embryos resulted in an aberrant morphology, including growth retardation, failure to switch from lordotic to fetal posture, and defective neural tube formation and neurogenesis. By expressing a wild-type p120ctn from the ROSA26 locus in p120ctn-null mouse embryonic stem cells, we could partially rescue neurogenesis. To further investigate the developmental role of p120ctn in neural tube formation, we generated conditional p120ctn fl/fl ;Wnt1Cre knockout mice. p120ctn deletion in Wnt1-expressing cells resulted in neural tube closure defects (NTDs) and craniofacial abnormalities. These defects could not be correlated with misregulation of brain marker genes or cell proliferation. In contrast, we found that p120ctn is required for proper expression of the cell adhesion components N-cadherin, E-cadherin and β-catenin, and of actin-binding proteins cortactin and Shroom3 at the apical side of neural folds. This region is of critical importance for closure of neural folds. Surprisingly, the lateral side of mutant neural folds showed loss of p120ctn, but not of N-cadherin, β-catenin or cortactin. Conclusions: These results indicate that p120ctn is required for neurogenesis and neurulation. Elimination of p120ctn in cells expressing Wnt1 affects neural tube closure by hampering correct formation of specific adhesion and actomyosin complexes at the apical side of neural folds. Collectively, our results demonstrate the crucial role of p120ctn during brain morphogenesis.

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“…Knockdown or loss of ␦-catenin leads to an increase in excitatory spine density accompanied by an increase of miniature excitatory postsynaptic current frequency (8,9,12). We sought to examine whether calpain-mediated cleavage of ␦-catenin affects the ability of ␦-catenin to regulate dendritic protrusion density in hippocampal neurons.…”

Section: Calpain-mediated Cleavage Of ␦-Catenin Regulates a Subset Ofmentioning

confidence: 99%

“…Furthermore, because the cadherin-catenin complex is linked to the actin cytoskeleton (3), the alterations in the interactions between ␦-catenin and cadherin could, in theory, promote signaling to the actin cytoskeleton thereby influencing protrusion density or stabilization. Similarly, because ␦-catenin associated with cadherin binds to several PDZ domain-containing synaptic proteins (12), it is possible that cleavage of ␦-catenin influences its association with PDZ domain scaffolding proteins thus impacting synapse assembly or disassembly.…”

Section: Proteolysis Of ␦-Catenin In Spine Remodelingmentioning

confidence: 99%

“…␦-Catenin is a cytosolic component of the complex and is predominantly expressed in the central nervous system (4 -6). We and others have identified critical roles for the protein in synaptic and dendritic architecture and function (7)(8)(9)(10)(11)(12)(13)(14). Mice lacking ␦-catenin have impaired learning and memory (15), suggesting that ␦-catenin is a critical component of the machinery underlying neural circuit formation and function.…”

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confidence: 99%

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A role for proteolytic regulation of δ-catenin in remodeling a subpopulation of dendritic spines in the rodent brain

Singh

Buescher

et al. 2018

Journal of Biological Chemistry

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Neural wiring and activity are essential for proper brain function and behavioral outputs and rely on mechanisms that guide the formation, elimination, and remodeling of synapses. During development, it is therefore vital that synaptic densities and architecture are tightly regulated to allow for appropriate neural circuit formation and function. δ-Catenin, a component of the cadherin-catenin cell adhesion complex, has been demonstrated to be a critical regulator of synaptic density and function in the developing central neurons. In this study, we identified forms of δ-catenin that include only the N-terminal (DcatNT) or the C-terminal (DcatCT) regions. We found that these δ-catenin forms are differentially expressed in different regions of the male mouse brain. Our results also indicated that in rat primary cortical culture, these forms are generated in an activity-dependent manner by Ca-dependent and calpain-mediated cleavage of δ-catenin or in an activity-independent but lysosome-dependent manner. Functionally, loss of the domain containing the calpain-cleavage sites allowing for generation of DcatCT and DcatNT perturbed the density of a subpopulation of dendritic protrusions in rat hippocampal neurons. This subpopulation likely included protrusions that are either in transition toward becoming mature mushroom spines or in the process of being eliminated. By influencing this subpopulation of spines, proteolytic processing of δ-catenin can likely regulate the balance between mature and immature dendritic protrusions in coordination with neural activity. We conclude that by undergoing cleavage, δ-catenin differentially regulates the densities of subpopulations of dendritic spines and contributes to proper neural circuit wiring in the developing brain.

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Functional roles of p120ctn family of proteins in central neurons

Cited by 20 publications

References 118 publications

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

The key genes, phosphoproteins, processes, and pathways affected by efavirenz‐activated CYP46A1 in the amyloid‐decreasing paradigm of efavirenz treatment

Neural defects caused by total and Wnt1-Cre mediated ablation of p120ctn in mice

A role for proteolytic regulation of δ-catenin in remodeling a subpopulation of dendritic spines in the rodent brain

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