Regulation of neuronal morphogenesis by 14-3-3epsilon (<i>Ywhae</i>) via the microtubule binding protein, doublecortin

Cornell, Brett; Wachi, Tomoka; Zhukarev, Vladimir; Toyo-oka, Kazuhito

doi:10.1093/hmg/ddw270

Cited by 48 publications

(54 citation statements)

References 40 publications

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“…Given their role, they are prevalent in several human diseases (Aghazadeh & Papadopoulos, ). YWHAG is highly expressed in brain, skeletal muscle and heart; mouse models suggest an alteration in Ywhag level lead to delayed neuronal migration in developing brain (Cornell, Wachi, Zhukarev, & Toyo‐Oka, ). ywhag1 knockdown in zebrafish show reduced brain size, cardiomegaly and increased cardiac arrhythmia.…”

Section: Introductionmentioning

confidence: 99%

Expanding the genotype–phenotype correlation ofde novoheterozygous missense variants inYWHAGas a cause of developmental and epileptic encephalopathy

Kanani

Titheradge

Cooper

et al. 2020

American J of Med Genetics Pt A

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Developmental and Epileptic encephalopathies (DEE) describe heterogeneous epilepsy syndromes, characterized by early‐onset, refractory seizures and developmental delay (DD). Several DEE associated genes have been reported. With increased access to whole exome sequencing (WES), new candidate genes are being identified although there are fewer large cohort papers describing the clinical phenotype in such patients. We describe 6 unreported individuals and provide updated information on an additional previously reported individual with heterozygous de novo missense variants in YWHAG. We describe a syndromal phenotype, report 5 novel, and a recurrent p.Arg132Cys YWHAG variant and compare developmental trajectory and treatment strategies in this cohort. We provide further evidence of causality in YWHAG variants. WES was performed in five patients via Deciphering Developmental Disorders Study and the remaining two were identified via Genematcher and AnnEX databases. De novo variants identified from exome data were validated using Sanger sequencing. Seven out of seven patients in the cohort have de novo, heterozygous missense variants in YWHAG including 2/7 patients with a recurrent c.394C > T, p.Arg132Cys variant; 1/7 has a second, pathogenic variant in STAG1. Characteristic features included: early‐onset seizures, predominantly generalized tonic–clonic and absence type (7/7) with good response to standard anti‐epileptic medications; moderate DD; Intellectual Disability (ID) (5/7) and Autism Spectrum Disorder (3/7). De novo YWHAG missense variants cause EE, characterized by early‐onset epilepsy, ID and DD, supporting the hypothesis that YWHAG loss‐of‐function causes a neurological phenotype. Although the exact mechanism of disease resulting from alterations in YWHAG is not fully known, it is possible that haploinsufficiency of YWHAG in developing cerebral cortex may lead to abnormal neuronal migration resulting in DEE.

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Section: Introductionmentioning

confidence: 99%

Expanding the genotype–phenotype correlation ofde novoheterozygous missense variants inYWHAGas a cause of developmental and epileptic encephalopathy

Kanani

Titheradge

Cooper

et al. 2020

American J of Med Genetics Pt A

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“…In utero electroporation was performed as previously described (40, 44, 47). Briefly, pregnant dams were anesthetized with Avatin and the uterine horn was exposed.…”

Section: Methodsmentioning

confidence: 99%

PEDF-Rpsa-Itga6 signaling regulates cortical neuronal morphogenesis

Blazejewski

Bennison

et al. 2020

Preprint

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16Neuromorphological defects underlie neurodevelopmental disorders and functional 17 defects. We identified a function for ribosomal protein SA (Rpsa) in regulating 18 neuromorphogenesis using in utero electroporation to knockdown Rpsa, which results in apical 19 dendrite misorientation, fewer/shorter extensions with decreased arborization, and decreased 20 spine density with altered spine morphology. We investigated Rpsa's ligand, pigment 21 epithelium-derived factor (PEDF), and interacting partner on the plasma membrane, Integrin 22 subunit α6 (Itga6). Rpsa, PEDF, and Itga6 knockdown cause similar phenotypes, with Rpsa and 23 Itga6 overexpression rescuing morphological defects in PEDF deficient neurons in vivo. 24 Additionally, Itga6 overexpression facilitates Rpsa expression on the membrane. GCaMP6s was 25 used to functionally analyze Rpsa knockdown via ex vivo calcium imaging. Rpsa deficient 26 neurons showed less fluctuation in fluorescence intensity, suggesting defective sub-threshold 27 calcium signaling. Our study identifies a role for PEDF-Rpsa-Itga6 signaling in 28 neuromorphogenesis, thus implicating these molecules in the etiology of neurodevelopmental 29 disorders and identifying them as potential therapeutic candidates.3 30 Author Summary 31Investigating the mechanisms that drive neuromorphogenesis is a crucial step towards 32 understanding normal and disordered brain development. We found that Rpsa signaling, which is 33 facilitated by Rpsa's ligand PEDF and its plasma membrane interaction partner Itga6, regulates 34 several key aspects of neuronal morphogenesis including dendritogenesis and dendritic spine 35 formation. We also found that PEDF-Rpsa-Itga6 signaling contributes to calcium signaling, 36 which is important for neuronal function. Furthermore, overexpression of Itga6 increased the 37 expression of Rpsa on the plasma membrane, where it binds extracellular ligands, suggesting that 38 Itga6 facilitates Rpsa signaling in this manner. Thus, PEDF, Rpsa, and Itga6 are implicated in the 39 etiology of neurodevelopmental disorders. This work is of particular relevance to Miller-Dieker 40 syndrome. The PEDF gene (Serpinf1) is located within a clinically relevant region of 41 chromosome 17p13.3 that is deleted in Miller-Dieker syndrome patients. Severe lissencephaly, 42 developmental delay, intellectual disability, and seizures are features of Miller-Dieker syndrome. 43 Further investigation of PEDF-Rpsa-Itga6 signaling may increase our understanding of the 44 mechanisms that contribute to MDS pathogenesis. 4 45 Introduction 46 Neuronal morphogenesis transforms an immature spherical neuron into a mature neuron 47 with a complex structure. Investigation of the mechanisms that drive neuromorphogenesis has 48 clear applications for improving treatments for neurodevelopmental disorders, as improper 49 neurite formation and dendritic development have been strongly associated with mental 50 retardation disorders and autism spectrum disorder (1-5). Inappropriate dendritic arborization 51 may also i...

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“…Timed pregnant mice were obtained by the set-up of the mating in the animal facility. In utero 181 electroporation (IUE) was performed as previously described (Cornell et al, 2016). Briefly, after 182 pregnant dams were anesthetized, the uterine horns were exposed, and one to two microliters of 183 plasmid mixed with 0.1% Fast Green were injected into the lateral ventricle of E15.5 embryo 184 brains by pulled-glass micropipette.…”

Section: In Utero Electroporation (Iue) 180mentioning

confidence: 99%

“…Neurite branching pattern was quantified using Sholl analysis in Fiji software as previously 248 described (Cornell et al, 2016). The center of soma was used as a reference, and the radius was 249 set to 200 or 250 m with 5 m interval.…”

Section: Sholl Analysis 247mentioning

confidence: 99%

Glutathione S-transferase Pi (Gstp) Proteins Regulate Neuritogenesis in the Developing Cerebral Cortex

Liu

Blazejewski

Bennison

et al. 2020

Preprint

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GSTP proteins are metabolic enzymes involved in removal of oxidative stress and intracellular signaling and also have inhibitory effects on JNK activity. However, the functions of Gstp proteins in the developing brain are unknown. In mice, there are three Gstp proteins, Gstp1, 2 and 3, while there is only one GSTP in humans. By RT-PCR analysis, we found that Gstp1 was expressed beginning at E15.5 in the cortex, but Gstp2 and 3 started expressing at E18.5. Gstp 1 and 2 knockdown caused decreased neurite number in cortical neurons, implicating them in neurite initiation. Using in utero electroporation to knockdown Gstp1 and 2 in layer 2/3 pyramidal neurons in vivo, we found abnormal swelling of the apical dendrite at P3 and reduced neurite number at P15. Using time-lapse live imaging, we found that the apical dendrite orientation was skewed compared to the control, but these defects were ameliorated. Overexpression of Gstp 1 or 2 resulted in changes in neurite length, suggesting a role in neurite elongation. We explored the molecular mechanism and found that JNK inhibition rescued reduced neurite number caused by Gstp knockdown, indicating that Gstp regulates neurite formation through JNK signaling. Thus, we found novel functions of Gstp proteins in neurite initiation during cortical development. Furthermore, the overexpression experiments suggest different functions of Gstp1 and 2 in neurite elongation. Since previous studies have shown the potential implication of Gstp in Autism Spectrum Disorder, our findings will attract more clinical interests in Gstp proteins in neurodevelopmental disorders.SignificanceNeurite formation, including neurite initiation and elongation, is the first step of generating polarized neuronal morphology in developing neurons, and thus is essential for establishing a neuronal network. Therefore, it is crucial to understand the mechanisms of neurite formation. Limited studies have been performed to clarify the mechanisms of neurite formation, especially neurite initiation. In this present study, we report a novel, essential role of Gstp in neurite initiation in mouse cortical neurons in vitro and in vivo. We also found that Gstp regulates neurite formation via JNK signaling pathways. These findings not only provide novel functions of Gstp proteins in neuritogenesis during cortical development but also help us to understand the complexity of neurite formation.

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Regulation of neuronal morphogenesis by 14-3-3epsilon (Ywhae) via the microtubule binding protein, doublecortin

Cited by 48 publications

References 40 publications

Expanding the genotype–phenotype correlation ofde novoheterozygous missense variants inYWHAGas a cause of developmental and epileptic encephalopathy

Expanding the genotype–phenotype correlation ofde novoheterozygous missense variants inYWHAGas a cause of developmental and epileptic encephalopathy

PEDF-Rpsa-Itga6 signaling regulates cortical neuronal morphogenesis

Glutathione S-transferase Pi (Gstp) Proteins Regulate Neuritogenesis in the Developing Cerebral Cortex

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