Somatic <i>Depdc5</i> deletion recapitulates electroclinical features of human focal cortical dysplasia type IIA

Hu, Shuntong; Knowlton, Robert C.; Watson, Brendon O.; Glanowska, Katarzyna M.; Murphy, Geoffrey G.; Parent, Jack M.; Wang, Yu

doi:10.1002/ana.25272

Cited by 46 publications

(66 citation statements)

References 22 publications

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“…Most of the experiments defining the components of the amino acid modulatory arm of the mTOR pathway have been performed in non‐neuronal cell lines. Recent studies in neurons, however, have shown how DEPDC5 and NPRL3 may modulate neural activity and epileptogenesis . A recent study demonstrated that knockdown of Depdc5 or Nprl3 caused mTOR‐dependent increases in cell size and process outgrowth in Neuro2a cells (N2a cells; a neuroblastoma cell line) and in mouse neural progenitor cell .…”

Section: Cell Biology Of the Gator1 Complexmentioning

confidence: 99%

“…Two recent studies using CRISPR‐editing of Depdc5 in the rodent cerebral cortex demonstrated abnormal electrical bursts and clinical seizures associated with experimentally induced FCD following CRISPR‐editing of Depdc5 by in utero electroporation . In a rat model two short guide RNAs (gRNAs) were used to target rat Depdc5 either at exon 8 or exon 12 by in utero electroporation on embryonic day 13. Analysis of these animals on postnatal day 21 revealed enlarged neuronal somata in association with hyperactivated mTORC1.…”

Section: Epileptogenesis and Mtor‐gator Signalingmentioning

confidence: 99%

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GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations

et al. 2019

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The mechanistic target of rapamycin (mTOR) pathway has been implicated in a growing number of malformations of cortical development (MCD) associated with intractable epilepsy. Mutations in single genes encoding mTOR pathway regulatory proteins have been linked to MCD such as focal cortical dysplasia (FCD) types IIa and IIb, hemimegalencephaly (HME), and megalencephaly. Recent studies have demonstrated that the GATOR1 protein complex, comprised of DEPDC5, NPRL3, and NPRL2, plays a pivotal role in regulating mTOR signaling in response to cellular amino acid levels and that mutations in DEPDC5, NPRL3, or NPRL2 are linked to FCD, HME, and seizures. Histopathological analysis of FCD and HME tissue specimens resected from individuals harboring DEPDC5, NPRL3, or NPRL2 gene mutations reveals hyperactivation of mTOR pathway signaling. Family pedigrees carrying mutations in either DEPDC5 or NPRL3 share clinical phenotypes of epilepsy and MCD, as well as intellectual and neuropsychiatric disabilities. Interestingly, some individuals with seizures associated with DEPDC5, NPRL3, or NPRL2 variants exhibit normal brain imaging suggesting either occult MCD or a role for these genes in non‐lesional neocortical epilepsy. Mouse models resulting from knockdown or knockout of either Depdc5 or Nprl3 exhibit altered cortical lamination, neuronal dysmorphogenesis, and enhanced neuronal excitability as reported in models resulting from direct mTOR activation through expression of its canonical activator RHEB. The role of the GATOR1 proteins in regulating mTOR signaling suggest plausible options for mTOR inhibition in the treatment of epilepsy associated with mutations in DEPDC5, NPRL3, or NPRL2.

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Section: Cell Biology Of the Gator1 Complexmentioning

confidence: 99%

Section: Epileptogenesis and Mtor‐gator Signalingmentioning

confidence: 99%

GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations

et al. 2019

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“…The specific morphology and dynamic behavior of oRG cells contribute to the proliferative expansion of the cortex and provide a scaffold upon which neuronal migration of the cortex depends. pathway in mouse models have identified phenotypic changes to neuronal size, morphology, and laminar position that resemble disease features of cortical malformations (Hu et al, 2018;Nguyen et al, 2019;Park et al, 2018). However, questions remain regarding the effects of mTOR dysregulation on progenitor cells as well as relevant differences between human and mouse cortical development.…”

Section: Introductionmentioning

confidence: 99%

mTOR signaling regulates the morphology and migration of outer radial glia in developing human cortex

Andrews

Subramanian

Kriegstein

2020

Preprint

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Outer radial glial (oRG) cells are a population of neural stem cells prevalent in the developing human cortex that contribute to its cellular diversity and evolutionary expansion. The mammalian Target of Rapamycin (mTOR) signaling pathway is active in human oRG cells. Mutations in mTOR pathway genes are linked to a variety of neurodevelopmental disorders and malformations of cortical development. We find that dysregulation of mTOR signaling specifically affects oRG cells, but not other progenitor types, by changing the actin cytoskeleton through the activity of the GTPase, CDC42. These effects change oRG cellular morphology, migration, and mitotic behavior. Thus, mTOR signaling can regulate the architecture of the developing human cortex by maintaining the cytoskeletal organization of oRG cells and the radial glia scaffold. Our study provides insight into how mTOR dysregulation may contribute to neurodevelopmental disease.

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“…In utero electroporation approaches offer an elegant means of modeling the effects of somatic mutations arising in the fetal cortex in a focal subset of neural cells at varying developmental time-points. CRISPR-mediated gene deletion of DEPDC5 in rats (Hu et al, 2018) and activation of mTOR signaling in mice using constitutively active mTOR kinase or Rheb proteins (Lim et al, 2015;Nguyen et al, 2019) have been shown to cause abnormal neuronal morphology and migration defects in the developing cortex. Furthermore, the severity of the seizure phenotype appears to correlate well with the extent of the electroporation, providing evidence linking the severity of malformations with the timing of the mutagenic event.…”

Section: Mtoropathies and Progenitor Cellsmentioning

confidence: 99%

Cortical Malformations: Lessons in Human Brain Development

Subramanian

Calcagnotto

Paredes

2020

Front. Cell. Neurosci.

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Creating a functional cerebral cortex requires a series of complex and well-coordinated developmental steps. These steps have evolved across species with the emergence of cortical gyrification and coincided with more complex behaviors. The presence of diverse progenitor cells, a protracted timeline for neuronal migration and maturation, and diverse neuronal types are developmental features that have emerged in the gyrated cortex. These factors could explain how the human brain has expanded in size and complexity. However, their complex nature also renders new avenues of vulnerability by providing additional cell types that could contribute to disease and longer time windows that could impact the composition and organization of the cortical circuit. We aim to discuss the unique developmental steps observed in human corticogenesis and propose how disruption of these species-unique processes could lead to malformations of cortical development.

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Somatic Depdc5 deletion recapitulates electroclinical features of human focal cortical dysplasia type IIA

Cited by 46 publications

References 22 publications

GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations

GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations

mTOR signaling regulates the morphology and migration of outer radial glia in developing human cortex

Cortical Malformations: Lessons in Human Brain Development

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