Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration

Schaffer, Ashleigh E.; Breuss, Martin; Çağlayan, Ahmet Okay; Al-Sanaa, Nouriya; Al-Abdulwahed, Hind Y.; Kaymakçalan, Hande; Yılmaz, Cahide; Zaki, Maha S.; Rosti, Rasim Özgür; Copeland, Brett; Baek, Seung Tae; Musaev, Damir; Scott, Eric; Ben‐Omran, Tawfeg; Kariminejad, Ariana; Kayserili, Hülya; Mojahedi, Faezeh; Kara, Majdi; Cai, Na; Silhavy, Jennifer L.; Elsharif, Seham; Fenercioğlu, Elif; Barshop, Bruce A.; Kara, Bülent; Wang, Rengang; Stanley, Valentina; James, Kiely N.; Nachnani, Rahul; Kalur, Aneesha; Megahed, Hisham; İncecik, Faruk; Danda, Sumita; Alanay, Yasemin; Faqeih, Eissa; Melikishvili, Gia; Mansour, Lobna; Miller, Ian; Sukhudyan, Biayna; Chelly, Jamel; Dobyns, William B.; Bilgüvar, Kaya; Jamra, Rami Abou; Günel, Murat; Gleeson, Joseph G.

doi:10.1038/s41588-018-0166-0

Cited by 75 publications

(64 citation statements)

References 46 publications

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“…The activity of the branched actin nucleation machinery and tension-sensing factors are coordinated to ensure that actin remodeling is responsive to local forces generated within the epithelium. Biallelic mutations in the human αN-catenin gene CTNNA2 is causative for a recessive form of pachygyria (reduction in gyrus formation) (Schaffer et al, 2018). This study and an earlier biochemical study (Drees et al, 2005) revealed that in addition to its role in coupling linear actin to the cadherin complex, α-catenin is able to regulate branched actin polymerization by competing with Arp2/3 for G-actin binding in migrating pyramidal neurons.…”

Section: Branched Actin -The Epicenter Of the Junctional Cytoskeletonmentioning

confidence: 57%

Adherens Junctions: Guardians of Cortical Development

Veeraval

O′Leary

Cooper

2020

Front. Cell Dev. Biol.

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Apical radial glia comprise the pseudostratified neuroepithelium lining the embryonic lateral ventricles and give rise to the extensive repertoire of pyramidal neuronal subtypes of the neocortex. The establishment of a highly apicobasally polarized radial glial morphology is a mandatory prerequisite for cortical development as it governs neurogenesis, neural migration and the integrity of the ventricular wall. As in all epithelia, cadherin-based adherens junctions (AJs) play an obligate role in the maintenance of radial glial apicobasal polarity and neuroepithelial cohesion. In addition, the assembly of resilient AJs is critical to the integrity of the neuroepithelium which must resist the tensile forces arising from increasing CSF volume and other mechanical stresses associated with the expansion of the ventricles in the embryo and neonate. Junctional instability leads to the collapse of radial glial morphology, disruption of the ventricular surface and cortical lamination defects due to failed neuronal migration. The fidelity of cortical development is therefore dependent on AJ assembly and stability. Mutations in genes known to control radial glial junction formation are causative for a subset of inherited cortical malformations (neuronal heterotopias) as well as perinatal hydrocephalus, reinforcing the concept that radial glial junctions are pivotal determinants of successful corticogenesis. In this review we explore the key animal studies that have revealed important insights into the role of AJs in maintaining apical radial glial morphology and function, and as such, have provided a deeper understanding of the aberrant molecular and cellular processes contributing to debilitating cortical malformations. We highlight the reciprocal interactions between AJs and the epithelial polarity complexes that impose radial glial apicobasal polarity. We also discuss the critical molecular networks promoting AJ assembly in apical radial glia and emphasize the role of the actin cytoskeleton in the stabilization of cadherin adhesion -a crucial factor in buffering the mechanical forces exerted as a consequence of cortical expansion.

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Section: Branched Actin -The Epicenter Of the Junctional Cytoskeletonmentioning

confidence: 57%

Adherens Junctions: Guardians of Cortical Development

Veeraval

O′Leary

Cooper

2020

Front. Cell Dev. Biol.

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“…Furthermore, a recent study by Schaffer et al . highlighted the importance of Arp2/3 regulation in a human disorder known as pachygyria, where a mutation in CTNNA2 leads to an overactivity in Arp2/3, resulting in disordered cortical neuronal migration . Silencing Arp2 and Arp3 in Jurkat T cells results in failure to spread on anti‐CD3‐coated coverslips, switches the F‐actin‐rich lamellipodia leading edge to polarized filopodia‐like structures, which established the link between the β2‐integrin activation and functional Arp2/3 .…”

Section: Introductionmentioning

confidence: 99%

Partial loss of actin nucleator actin‐related protein 2/3 activity triggers blebbing in primary T lymphocytes

Obeidy

Oehlers

et al. 2019

Immunol Cell Biol

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T lymphocytes utilize amoeboid migration to navigate effectively within complex microenvironments. The precise rearrangement of the actin cytoskeleton required for cellular forward propulsion is mediated by actin regulators, including the actin-related protein 2/3 (Arp2/3) complex, a macromolecular machine that nucleates branched actin filaments at the leading edge. The consequences of modulating Arp2/3 activity on the biophysical properties of the actomyosin cortex and downstream T cell function are incompletely understood. We report that even a moderate decrease of Arp3 levels in T cells profoundly affects actin cortex integrity. Reduction in total F-actin content leads to reduced cortical tension and disrupted lamellipodia formation. Instead, in Arp3-knockdown cells, the motility mode is dominated by blebbing migration characterized by transient, balloon-like protrusions at the leading edge. Although this migration mode seems to be compatible with interstitial migration in three-dimensional environments, diminished locomotion kinetics and impaired cytotoxicity interfere with optimal T cell function. These findings define the importance of finely tuned, Arp2/3-dependent mechanophysical membrane integrity in cytotoxic effector T lymphocyte activities.

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“…At 2 h, genes like catenin beta-2 (ctnnb2), serine/threonine-protein kinase ULK1 (ulk1), ephrin type-A receptor 8 (epha8), and gamma-aminobutyric acid receptor-associated protein (gabarap), associated with the generation of new neurites (Okazaki et al, 2000;Coyle et al, 2002;Gu et al, 2005;Lin et al, 2009), are highly suppressed. At 4 h the same pattern is observed, with suppression of genes like catenin alpha-2 (ctnna2; Schaffer et al, 2018), clathrin coat assembly protein AP180 (snap91; Bushlin et al, 2008), and protein furry homolog-like (fryl; Hayette et al, 2005). This contrasts with the late expression peak of neurite development genes like contactin-associated proteinlike 2 (cntnap2; Poliak et al, 1999), brain-specific angiogenesis inhibitor 1-associated protein 2 (baiap2; Kang et al, 2016), and protein furry homolog (fry; Hayette et al, 2005) at 24 h. These neuron projection development (GO:0031175) genes are also cytoskeletal modification genes.…”

Section: Structural Modificationmentioning

confidence: 58%

Temporal Profile of Brain Gene Expression After Prey Catching Conditioning in an Anuran Amphibian

2020

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A key goal in modern neurobiology is to understand the mechanisms underlying learning and memory. To that end, it is essential to identify the patterns of gene expression and the temporal sequence of molecular events associated with learning and memory processes. It is also important to ascertain if and how these molecular events vary between organisms. In vertebrates, learning and memory processes are characterized by distinct phases of molecular activity involving gene transcription, structural change, and long-term maintenance of such structural change in the nervous system. Utilizing next generation sequencing techniques, we profiled the temporal expression patterns of genes in the brain of the fire-bellied toad Bombina orientalis after prey catching conditioning. The fire-bellied toad is a basal tetrapod whose neural architecture and molecular pathways may help us understand the ancestral state of learning and memory mechanisms in tetrapods. Differential gene expression following conditioning revealed activity in molecular pathways related to immediate early genes (IEG), cytoskeletal modification, axon guidance activity, and apoptotic processes. Conditioning induced early IEG activity coinciding with transcriptional activity and neuron structural modification, followed by axon guidance and cell adhesion activity, and late neuronal pruning. While some of these gene expression patterns are similar to those found in mammals submitted to conditioning, some interesting divergent expression profiles were seen, and differential expression of some well-known learning-related mammalian genes is missing altogether. These results highlight the importance of using a comparative approach in the study of the mechanisms of leaning and memory and provide molecular resources for a novel vertebrate model in the relatively poorly studied Amphibia.

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Biallelic loss of human CTNNA2, encoding αN-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration

Cited by 75 publications

References 46 publications

Adherens Junctions: Guardians of Cortical Development

Adherens Junctions: Guardians of Cortical Development

Partial loss of actin nucleator actin‐related protein 2/3 activity triggers blebbing in primary T lymphocytes

Temporal Profile of Brain Gene Expression After Prey Catching Conditioning in an Anuran Amphibian

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