Inactivation of mTORC1 in the Developing Brain Causes Microcephaly and Affects Gliogenesis

Cloëtta, Dimitri; Thomanetz, Venus; Baranek, Constanze; Lustenberger, Regula Maria; Lin, Shuo; Oliveri, Filippo; Atanasoski, Suzana; Rüegg, Markus A.

doi:10.1523/jneurosci.3294-12.2013

Cited by 124 publications

(112 citation statements)

References 58 publications

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“…A recent study showed that neuron-specific inactivation of mTORC2 following Rictor KO resulted in a small brain, including a small cerebellum, although the development of the medial IGL was normal . Meanwhile, another study revealed that neuron-specific inactivation of mTORC1 following Rptor KO resulted in microcephaly and lethality within a few hours of birth, prior to the completion of cerebellar development (Cloetta et al, 2013). These reports exclude the involvement of mTORC2, but not of mTORC1, signaling in CGNs of the medial cerebellum.…”

Section: Discussionmentioning

confidence: 97%

“…These reports exclude the involvement of mTORC2, but not of mTORC1, signaling in CGNs of the medial cerebellum. Rptor-KO mice also exhibit reduced Map2 staining and reduced dendritic complexity in the cerebral cortex (Cloetta et al, 2013). Additionally, Mid1 has been reported to regulate the interaction between mTOR and raptor (Liu et al, 2011), and to regulate microtubule-associated mRNA transport and protein translation (Aranda-Orgillés et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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Novel role of Rac-Mid1 signaling in medial cerebellar development

et al. 2017

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Rac signaling impacts a relatively large number of downstream targets; however, few studies have established an association between Rac pathways and pathological conditions. In the present study, we generated mice with double knockout of Rac1 and Rac3 (Atoh1-Cre;Rac1 flox/flox ;Rac3 −/− ) in cerebellar granule neurons (CGNs). We observed impaired tangential migration at E16.5, as well as numerous apoptotic CGNs at the deepest layer of the external granule layer (EGL) in the medial cerebellum of Atoh1-Cre; Rac1 flox/flox ;Rac3 −/− mice at P8. Atoh1-Cre;Rac1 flox/flox ;Rac3CGNs differentiated normally until expression of p27 kip1 and NeuN in the deep EGL at P5. Primary CGNs and cerebellar microexplants from Atoh1-Cre;Rac1 flox/flox ;Rac3 −/− mice exhibited impaired neuritogenesis, which was more apparent in Map2-positive dendrites. Such findings suggest that impaired tangential migration and final differentiation of CGNs have resulted in decreased cerebellum size and agenesis of the medial internal granule layer, respectively. Furthermore, Rac depleted/deleted cells exhibited decreased levels of Mid1 and impaired mTORC1 signaling. Mid1 depletion in CGNs produced mild impairments in neuritogenesis and reductions in mTORC1 signaling. Thus, a novel Rac-signaling pathway (Rac1-Mid1-mTORC1) may be involved in medial cerebellar development.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Novel role of Rac-Mid1 signaling in medial cerebellar development

et al. 2017

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“…Hyperactivation of mTORC1 by TSC1/2 deletion induces aberrant growth, proliferation, and differentiation of neurons and astrocytes, resulting in neuronal dysplasia, abnormal neuronal architecture, reactive astrogliosis, and seizures (27, 40 -42). Inactivation of mTORC1 in neuronal progenitors impairs the growth and proliferation of neurons and astrocytes, resulting in a smaller brain and in death shortly after birth (25,43).…”

Section: Discussionmentioning

confidence: 99%

“…However, whether altered mTORC1 signaling is a cause or consequence of these pathologies has not been determined. Deletion of the mTORC1-specific component Raptor in neural progenitors in mice reduced the size and number of neurons and astrocytes and led to a deficit in glial differentiation and microcephaly in mice (25). Therefore, the role of mTORC1 in adult neurons is not known.…”

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confidence: 99%

Neuronal mTORC1 Is Required for Maintaining the Nonreactive State of Astrocytes

Zhang

Liang

et al. 2017

Journal of Biological Chemistry

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Edited by F. Anne StephensonAstrocytes respond to CNS insults through reactive astrogliosis, but the underlying mechanisms are unclear. In this study, we show that inactivation of mechanistic target of rapamycin complex (mTORC1) signaling in postnatal neurons induces reactive astrogliosis in mice. Ablation of Raptor (an mTORC1-specific component) in postmitotic neurons abolished mTORC1 activity and produced neurons with smaller soma and fewer dendrites, resulting in microcephaly and aberrant behavior in adult mice. Interestingly, extensive astrogliosis without significant astrocyte proliferation and glial scar formation was observed in these mice. The inhibition of neuronal mTORC1 may activate astrogliosis by reducing neuron-derived fibroblast growth factor 2 (FGF-2), which might trigger FGF receptor signaling in astrocytes to maintain their nonreactive state, and FGF-2 injection successfully prevented astrogliosis in Raptor knock-out mice. This study demonstrates that neuronal mTORC1 inhibits reactive astrogliosis and plays an important role in CNS pathologies.

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“…14 Moreover, mTOR inactivation caused microcephaly and disruption of peripheral nerve growth in mice. 15,16 Taken together, the well-controlled PI3KeAKTsemTOR signaling pathway is important in normal development. In megalencephalic brains of HME, FCD, and TSC, we previously described immaturity and mis-positioning of cortical neurons.…”

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confidence: 99%

Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay

Hanai

Sukigara

Dai

et al. 2017

The American Journal of Pathology

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The activation of phosphatidylinositol 3-kinase-AKTs-mammalian target of rapamycin cell signaling pathway leads to cell overgrowth and abnormal migration and results in various types of cortical malformations, such as hemimegalencephaly (HME), focal cortical dysplasia, and tuberous sclerosis complex. However, the pathomechanism underlying abnormal cell migration remains unknown. With the use of fetal mouse brain, we performed causative gene analysis of the resected brain tissues from a patient with HME and investigated the pathogenesis. We obtained a novel somatic mutation of the MTOR gene, having approximately 11% and 7% mutation frequency in the resected brain tissues. Moreover, we revealed that the MTOR mutation resulted in hyperphosphorylation of its downstream molecules, S6 and 4E-binding protein 1, and delayed cell migration on the radial glial fiber and did not affect other cells. We suspect cell-autonomous migration arrest on the radial glial foot by the active MTOR mutation and offer potential explanations for why this may lead to cortical malformations such as HME.

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Inactivation of mTORC1 in the Developing Brain Causes Microcephaly and Affects Gliogenesis

Cited by 124 publications

References 58 publications

Novel role of Rac-Mid1 signaling in medial cerebellar development

Novel role of Rac-Mid1 signaling in medial cerebellar development

Neuronal mTORC1 Is Required for Maintaining the Nonreactive State of Astrocytes

Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay

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