Disruption of CTNND2, encoding delta-catenin, causes a penetrant attention deficit disorder and myopia

Adegbola, Abidemi; Lutz, Richard E.; Nikkola, Elina; Strom, Samuel P.; Picker, Jonathan; Wynshaw‐Boris, Anthony

doi:10.1016/j.xhgg.2020.100007

Cited by 6 publications

(7 citation statements)

References 76 publications

(51 reference statements)

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“…In the brain, delta-catenin can additionally be found as a longer isoform that contains an extra coiled-coil within its N-terminal tail ( Markham et al, 2014 ). While delta-catenin has four transcript variants, only the longest one contains the coiled-coil domain ( Adegbola et al, 2020 ). A schematic of delta-catenin’s protein structure is shown in Figure 1 .…”

Section: Introductionmentioning

confidence: 99%

Delta-Catenin as a Modulator of Rho GTPases in Neurons

Donta

Srivastava

McCrea

2022

Front. Cell. Neurosci.

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Small Rho GTPases are molecular switches that are involved in multiple processes including regulation of the actin cytoskeleton. These GTPases are activated (turned on) and inactivated (turned off) through various upstream effector molecules to carry out many cellular functions. One such upstream modulator of small Rho GTPase activity is delta-catenin, which is a protein in the p120-catenin subfamily that is enriched in the central nervous system. Delta-catenin affects small GTPase activity to assist in the developmental formation of dendrites and dendritic spines and to maintain them once they mature. As the dendritic arbor and spine density are crucial for synapse formation and plasticity, delta-catenin’s ability to modulate small Rho GTPases is necessary for proper learning and memory. Accordingly, the misregulation of delta-catenin and small Rho GTPases has been implicated in several neurological and non-neurological pathologies. While links between delta-catenin and small Rho GTPases have yet to be studied in many contexts, known associations include some cancers, Alzheimer’s disease (AD), Cri-du-chat syndrome, and autism spectrum disorder (ASD). Drawing from established studies and recent discoveries, this review explores how delta-catenin modulates small Rho GTPase activity. Future studies will likely elucidate how PDZ proteins that bind delta-catenin further influence small Rho GTPases, how delta-catenin may affect small GTPase activity at adherens junctions when bound to N-cadherin, mechanisms behind delta-catenin’s ability to modulate Rac1 and Cdc42, and delta-catenin’s ability to modulate small Rho GTPases in the context of diseases, such as cancer and AD.

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Section: Introductionmentioning

confidence: 99%

Delta-Catenin as a Modulator of Rho GTPases in Neurons

Donta

Srivastava

McCrea

2022

Front. Cell. Neurosci.

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“…Importantly, genetic studies identify a loss of δ-catenin functions as a significant factor for both the Cri-du-chat syndrome and ASD (21, 84–86). Moreover, altered δ-catenin functions have been implicated in many other neurological disorders, including cerebral palsy, schizophrenia, anxiety disorders, Alzheimer’s disease, and attention deficit hyperactivity disorder (87–91). Therefore, our findings likely lead to an understanding of shared etiology and pathophysiology among these diseases.…”

Section: Discussionmentioning

confidence: 99%

The autism-associated loss of δ-catenin functions disrupts social behaviors

Mendez-Vazquez¹,

Roach²,

Nip³

et al. 2023

Preprint

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δ–catenin is expressed in excitatory synapses and functions as an anchor for the glutamatergic AMPA receptor (AMPAR) GluA2 subunit in the postsynaptic density. The glycine 34 to serine (G34S) mutation in theδ–cateningene is found in autism spectrum disorder (ASD) patients and induces loss of δ–catenin functions at excitatory synapses, which is presumed to underlie ASD pathogenesis in humans. However, how the G34S mutation causes loss of δ–catenin functions to induce ASD remains unclear. Here, using neuroblastoma cells, we discover that the G34S mutation generates an additional phosphorylation site for glycogen synthase kinase 3β (GSK3β). This promotes δ–catenin degradation and causes the reduction of δ–catenin levels, which likely contributes to the loss of δ–catenin functions. Synaptic δ–catenin and GluA2 levels in the cortex are significantly decreased in mice harboring the δ–catenin G34S mutation. The G34S mutation increases glutamatergic activity in cortical excitatory neurons while it is decreased in inhibitory interneurons, indicating changes in cellular excitation and inhibition. δ–catenin G34S mutant mice also exhibit social dysfunction, a common feature of ASD. Most importantly, inhibition of GSK3β activity reverses the G34S-induced loss of δ–catenin function effects in cells and mice. Finally, using δ–catenin knockout mice, we confirm that δ–catenin is required for GSK3β inhibition-induced restoration of normal social behaviors in δ–catenin G34S mutant animals. Taken together, we reveal that the loss of δ–catenin functions arising from the ASD-associated G34S mutation induces social dysfunction via alterations in glutamatergic activity and that GSK3β inhibition can reverse δ–catenin G34S-induced synaptic and behavioral deficits.

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“…In recent years, more and more studies have shown that the expression of δ-catenin is up-regulated in some epithelial tumors [5][6][7][8] . Since δ-catenin contains multiple structural domains and is located at a key point of the signaling pathway at the molecular level, it is involved in and affects the occurrence and development of diseases in multiple ways [31][32][33] . It has been speculated that the increased expression of δ-catenin gene level in tumors may be related to multiple mechanisms [31][32][33][34][35][36] : (1) δ-catenin can regulate the expression levels of apoptosis-related proteins, such as Bcl-2L, surviving, cleaved caspase 3.…”

Section: Discussionmentioning

confidence: 99%

“…Since δ-catenin contains multiple structural domains and is located at a key point of the signaling pathway at the molecular level, it is involved in and affects the occurrence and development of diseases in multiple ways [31][32][33] . It has been speculated that the increased expression of δ-catenin gene level in tumors may be related to multiple mechanisms [31][32][33][34][35][36] : (1) δ-catenin can regulate the expression levels of apoptosis-related proteins, such as Bcl-2L, surviving, cleaved caspase 3. It can also promote the proliferation of tumor cells and inhibit apoptosis; (2) δ-catenin protein may be related to its ability to stimulate the secretion of vasoactive factors in tumor tissues and participate in neovascularization.…”

Section: Discussionmentioning

confidence: 99%

The effect of δ (delta)-catenin on small-world brain network properties in breast cancer patients before chemotherapy

Xue

Cao

et al. 2023

Preprint

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Our study is to investigate the effect of δ-catenin on the alterations in small-world brain network before chemotherapy in breast cancer patients by rs-fMRI, based on the hypothesis that different δ-catenin expressions have independent brain imaging characteristics. A total of 105 cases of pathologically confirmed breast cancer were collected and divided into high δ-catenin expression (DH, 52 cases) and low expression (DL, 53 cases) groups. Also, 36 healthy women matched for age were enrolled as a healthy control group (HC). The results show differences in several network topology attributes among the three groups. Furthermore, in addition to differences in nodal efficiency, betweenness and degree centrality metrics between the patient group and HC in multiple brain regions, there were also alterations between the DL and DH groups in brain regions such as the supramarginal and inferior frontal gyrus, which supports our hypothesis. Neuropsychological scores also showed that the DL group had significantly shorter short and long-term memory times than the DH group. The study concluded that different states of δ-catenin had significantly different effects on the attributes of the breast cancer patients' brain network and had characteristic impacts on some brain regions. They could also be involved in executive function-related cognitive functions and changes in regulating emotions.

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Disruption of CTNND2, encoding delta-catenin, causes a penetrant attention deficit disorder and myopia

Cited by 6 publications

References 76 publications

Delta-Catenin as a Modulator of Rho GTPases in Neurons

Delta-Catenin as a Modulator of Rho GTPases in Neurons

The autism-associated loss of δ-catenin functions disrupts social behaviors

The effect of δ (delta)-catenin on small-world brain network properties in breast cancer patients before chemotherapy

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