Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse

Division of Medical Genetics, Department of Pediatrics, University of Texas Health Science Center, Houston, TX 77030, USA.
Human Molecular Genetics (Impact Factor: 6.39). 02/2009; 18(7):1252-65. DOI: 10.1093/hmg/ddp025
Source: PubMed


Tuberous sclerosis complex (TSC) is an autosomal dominant, tumor predisposition disorder characterized by significant neurodevelopmental brain lesions, such as tubers and subependymal nodules. The neuropathology of TSC is often associated with seizures and intellectual disability. To learn about the developmental perturbations that lead to these brain lesions, we created a mouse model that selectively deletes the Tsc2 gene from radial glial progenitor cells in the developing cerebral cortex and hippocampus. These Tsc2 mutant mice were severely runted, developed post-natal megalencephaly and died between 3 and 4 weeks of age. Analysis of brain pathology demonstrated cortical and hippocampal lamination defects, hippocampal heterotopias, enlarged dysplastic neurons and glia, abnormal myelination and an astrocytosis. These histologic abnormalities were accompanied by activation of the mTORC1 pathway as assessed by increased phosphorylated S6 in brain lysates and tissue sections. Developmental analysis demonstrated that loss of Tsc2 increased the subventricular Tbr2-positive basal cell progenitor pool at the expense of early born Tbr1-positive post-mitotic neurons. These results establish the novel concept that loss of function of Tsc2 in radial glial progenitors is one initiating event in the development of TSC brain lesions as well as underscore the importance of Tsc2 in the regulation of neural progenitor pools. Given the similarities between the mouse and the human TSC lesions, this model will be useful in further understanding TSC brain pathophysiology, testing potential therapies and identifying other genetic pathways that are altered in TSC.

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Available from: Sharon Win Way
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    • "Several lines of evidence support a direct pathogenic role of migration defects in the cortical malformations found in TSC patients. First, lamination defects have been reported in Tsc1 and 2 mutant mouse models (Carson et al., 2012; Way et al., 2009). Second, Tsc1 deletion from "
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    ABSTRACT: Tuberous sclerosis complex (TSC) is associated with neurodevelopmental abnormalities, including defects in neuronal migration. However, the alterations in cell signaling mechanisms critical for migration and final positioning of neurons in TSC remain unclear. Our detailed cellular analyses reveal that reduced Tsc2 in newborn neurons causes abnormalities in leading processes of migrating neurons, accompanied by significantly delayed migration. Importantly, we demonstrate that Reelin-Dab1 signaling is aberrantly regulated in TSC mouse models and in cortical tubers from TSC patients owing to enhanced expression of the E3 ubiquitin ligase Cul5, a known mediator of pDab1 ubiquitination. Likewise, mTORC1 activation by Rheb overexpression generates similar neuronal and Reelin-Dab1 signaling defects, and directly upregulates Cul5 expression. Inhibition of mTORC1 by rapamycin treatment or by reducing Cul5 largely restores normal leading processes and positioning of migrating neurons. Thus, disrupted Reelin-Dab1 signaling is critically involved in the neuronal migration defects of TSC. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Jul 2015 · Cell Reports
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    • "Loss of both alleles of Tsc1 or Tsc2 in mice impairs neuronal migration [24, 25], while haploinsufficiency leads to disrupted connectivity between retinal neurons and their thalamic targets [26]. Tsc1 or Tsc2 mutant animals also have reduced CNS myelination [25, 27]. Thus far, the Tsc2+/− mouse has demonstrated deficits in hippocampal-dependent learning and social communication without the presence of the epileptic seizures that are proposed to trigger these neuropsychological symptoms [17, 18]. "
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    ABSTRACT: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by tumor growth and neuropsychological symptoms such as autistic behavior, developmental delay, and epilepsy. While research has shed light on the biochemical and genetic etiology of TSC, the pathogenesis of the neurologic and behavioral manifestations remains poorly understood. TSC patients have a greatly increased risk of developmental delay and autism spectrum disorder, rendering the relationship between the two sets of symptoms an extremely pertinent issue for clinicians. We have expanded on previous observations of aberrant vocalizations in Tsc2 +/− mice by testing vocalization output and developmental milestones systematically during the early postnatal period. In this study, we have demonstrated that Tsc2 haploinsufficiency in either dams or their pups results in a pattern of developmental delay in sensorimotor milestones and ultrasonic vocalizations.
    Full-text · Article · Aug 2014
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    • "In fact, so-called “two-hit” mechanisms of germline mutation and somatic mutation have been proposed for human tubers of TSC patients (Crino et al., 2010), although another report argued that the second hit was rare (Qin et al., 2010). The two-hit mechanism has been evaluated with homozygous deletion of TSC2 only in radial glia, and heterozygous deletion in all other cells by crossing Tsc2+/-, Tsc2flox, and GFAP-Cre mice (Way et al., 2009). The mice showed cytomegaly, defects in lamination, astrogliosis, and hypomyelination. "
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    ABSTRACT: Target of rapamycin (TOR) was first identified in yeast as a target molecule of rapamycin, an anti-fugal and immunosuppressant macrolide compound. In mammals, its orthologue is called mammalian TOR (mTOR). mTOR is a serine/threonine kinase that converges different extracellular stimuli, such as nutrients and growth factors, and diverges into several biochemical reactions, including translation, autophagy, transcription, and lipid synthesis among others. These biochemical reactions govern cell growth and cause cells to attain an anabolic state. Thus, the disruption of mTOR signaling is implicated in a wide array of diseases such as cancer, diabetes, and obesity. In the central nervous system, the mTOR signaling cascade is activated by nutrients, neurotrophic factors, and neurotransmitters that enhances protein (and possibly lipid) synthesis and suppresses autophagy. These processes contribute to normal neuronal growth by promoting their differentiation, neurite elongation and branching, and synaptic formation during development. Therefore, disruption of mTOR signaling may cause neuronal degeneration and abnormal neural development. While reduced mTOR signaling is associated with neurodegeneration, excess activation of mTOR signaling causes abnormal development of neurons and glia, leading to brain malformation. In this review, we first introduce the current state of molecular knowledge of mTOR complexes and signaling in general. We then describe mTOR activation in neurons, which leads to translational enhancement, and finally discuss the link between mTOR and normal/abnormal neuronal growth during development.
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