Activating the translational repressor 4E-BP or reducing S6K-GSK3β activity prevents accelerated axon growth induced by hyperactive mTOR<i>in vivo</i>

Gong, Xuan; Zhang, Longbo; Huang, Tianxiang; Lin, Tiffany V.; Miyares, Laura; Wen, John H.; Hsieh, Lawrence S.; Bordey, Angélique

doi:10.1093/hmg/ddv295

Cited by 35 publications

(39 citation statements)

References 64 publications

(83 reference statements)

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“…Given that elevated cortical p-S6 and CRMP2, and rescue by S6K1 inhibitor treatment, all occur during the early postnatal life, we predict that the initial growth of subcortical-projecting neurons is over-exuberant in Pten +/− mice. This would be consistent with reports of Pten and mTOR-S6K signalling acting as regulators of axonal growth711. Another factor that could be at play is reduced axonal pruning of subcortical-projecting neurons in Pten +/− mice.…”

Section: Discussionsupporting

confidence: 92%

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Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome

2016

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Multiple autism risk genes converge on the regulation of mTOR signalling, which is a key effector of neuronal growth and connectivity. We show that mTOR signalling is dysregulated during early postnatal development in the cerebral cortex of germ-line heterozygous Pten mutant mice (Pten+/−), which model macrocephaly/autism syndrome. The basolateral amygdala (BLA) receives input from subcortical-projecting neurons in the medial prefrontal cortex (mPFC). Analysis of mPFC to BLA axonal projections reveals that Pten+/− mice exhibit increased axonal branching and connectivity, which is accompanied by increased activity in the BLA in response to social stimuli and social behavioural deficits. The latter two phenotypes can be suppressed by pharmacological inhibition of S6K1 during early postnatal life or by reducing the activity of mPFC–BLA circuitry in adulthood. These findings identify a mechanism of altered connectivity that has potential relevance to the pathophysiology of macrocephaly/autism syndrome and autism spectrum disorders featuring dysregulated mTOR signalling.

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Section: Discussionsupporting

confidence: 92%

“…Phosphorylated rpS6 (p-S6) is a readout for mTORC1 signalling, and has been shown to regulate cell size4. Moreover, studies in the mammalian nervous system have shown that mTOR-S6K signalling regulates neuronal soma size, dendritic arborization, axonal growth and connectivity567.…”

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confidence: 99%

Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome

2016

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“…Patch‐clamp recordings in the animals reveal increased cell capacitance and decreased membrane resistance in the Rheb CA model. Astrogliosis and microglial activation, and increased axonal length, are observed in the Rheb CA ‐model and in the Depdc5 flox/flox ‐Syn1 Cre mouse . Of interest, as in Tsc2 cKO mice, the degree of mTOR hyperactivity correlates with the severity of epilepsy and associated neuropathology including soma size and misplacement Rheb CA plasmid model .…”

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 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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“…A construct expressing an shRNA against both S6K1 and S6K2 (shS6K1/2, previously used by our laboratory to normalize Rheb CA effects on axon length [35]) was coelectroporated with Rheb CA ; an empty vector was coelectroporated as a control (Fig. S7A).…”

Section: Significancementioning

confidence: 99%

Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration

Lin

Hsieh

Kimura

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hyperactive mammalian target of rapamycin complex 1 (mTORC1) is a shared molecular hallmark in several neurodevelopmental disorders characterized by abnormal brain cytoarchitecture. The mechanisms downstream of mTORC1 that are responsible for these defects remain unclear. We show that focally increasing mTORC1 activity during late corticogenesis leads to ectopic placement of upper-layer cortical neurons that does not require altered signaling in radial glia and is accompanied by changes in layer-specific molecular identity. Importantly, we found that decreasing cap-dependent translation by expressing a constitutively active mutant of the translational repressor eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) prevents neuronal misplacement and soma enlargement, while partially rescuing dendritic hypertrophy induced by hyperactive mTORC1. Furthermore, overactivation of translation alone through knockdown of 4E-BP2 was sufficient to induce neuronal misplacement. These data show that many aspects of abnormal brain cytoarchitecture can be prevented by manipulating a single intracellular process downstream of mTORC1, cap-dependent translation.veractive mammalian target of rapamycin complex 1 (mTORC1) signaling is a signature of many disorders with cortical malformations (1), ranging from tuberous sclerosis complex with focal dysplasias to hemimegalencephaly with more diffuse, hemispheric aberrations. The high incidence of negative outcomes in individuals with such malformations (2), which are often associated with intractable childhood seizures, underscores the need to better understand the molecular etiology of these developmental lesions. Animal models have demonstrated the causative effect of increased mTORC1 signaling on mislamination (3-7). The pharmacological mTORC1 blocker rapamycin has also been shown to reverse some of the developmental abnormalities and associated seizure activity in several of these mouse models (5, 6, 8-10), further emphasizing the importance of mTORC1 in the disease pathogenesis.Despite the demonstrated relevance of mTORC1 signaling, there is less known about the molecular mechanisms by which mTORC1 alters cortical development. Addressing this question is complicated by the wide range of cellular processes regulated by mTORC1 through independent downstream targets. Among these regulated processes are autophagy, lysosomal function, lipid synthesis, and, one of the best-studied functions, cap-dependent translation (11). Because current drugs that suppress mTORC1 activity can have serious side effects (12, 13) and do not fully block some of mTORC1's functions (14), a more specific understanding of how mTORC1 contributes to cortical mislamination could yield better targets for treatment.This study therefore aimed to more closely characterize the cytoarchitectural aberrations generated by hyperactive mTORC1 and to examine the contribution of translational regulation to these cortical malformations. Using in utero electroporation, we generated and characterized focal mislamination an...

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Activating the translational repressor 4E-BP or reducing S6K-GSK3β activity prevents accelerated axon growth induced by hyperactive mTORin vivo

Cited by 35 publications

References 64 publications

Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome

Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome

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

Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration

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