Roles of mTOR Signaling in Brain Development

Lee, Da Yong

doi:10.5607/en.2015.24.3.177

Cited by 117 publications

(88 citation statements)

References 76 publications

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“…This remains in line with a previous report by other authors who also observed changes in mTOR level with age (Choi et al, 2016). The relatively low level of mTOR at birth in intubated groups might be related to the disruptive effect of prenatal stress and ethanol administration on the role of mTOR in the process of neuronal and glial differentiation during the third trimester (Lee, 2015). The mTOR level continued to be significantly lower in the fetal-ethanol pups throughout the whole brain spurt period when an intensive neurogenesis and cell growth still take place.…”

Section: Discussionsupporting

confidence: 92%

Prenatal ethanol intoxication and maternal intubation stress alter cell survival and apoptosis in the postnatal development of rat hippocampus

Elibol

Beker

Şahbaz

et al. 2019

Acta Neurobiologiae Experimentalis

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It is well known that the fetal ethanol exposure and prenatal stress may have adverse effects on brain development. Interestingly, some morphological and functional recovery from their teratogenic effects that take place during brain maturation. However, mechanisms that underlie this recovery are not fully elucidated. The aim of this study was to examine whether the postnatal attenuation of fetal alcohol -and maternal stress-induced morphological and functional deficits correlates with compensatory changes in the expression/activation of the brain proteins involved in inflammation, cell survival and apoptosis. In this project, we investigated the hippocampus which belongs to the brain regions most susceptible to the adverse effects of prenatal ethanol exposure. Pregnant rat dams were administered ethanol (A) or isocaloric glucose solution (IC) by a gastric intubation during gestational days 7-20. The pure control group received ad libitum laboratory chow and water with no other treatment. The hippocampi of fetal-ethanol and control pups were examined at the postnatal day (PD)1, PD10, PD30 and PD60. Moderate fetal-ethanol exposure and prenatal intubation stress caused a significant increase in molecular factors relating to inflammation (iNOS) and cell survival/apoptosis pathways (PTEN, GSK-3 and ERK) at birth, with a rapid compensation from these developmental deficits upon removal of alcohol at PD10. Indeed, an increase in ERK1/2 and JNK1/2 activation at PD30 was observed with ethanol consumption. It indicates that the recovery process in A and IC brains started soon after the birth upon the ethanol and stressor withdrawal and continued until the adulthood.

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Section: Discussionsupporting

confidence: 92%

Prenatal ethanol intoxication and maternal intubation stress alter cell survival and apoptosis in the postnatal development of rat hippocampus

Elibol

Beker

Şahbaz

et al. 2019

Acta Neurobiologiae Experimentalis

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“…rapamycin" (mTOR) (4,40). These mutations in mice lead to a behavioral phenotype resembling autism (41), and targeting the mTOR pathway has been shown to reverse autism-like behavior (42,43).…”

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confidence: 99%

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Patel

Tsilioni

Leeman

et al. 2016

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

112

104

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We had reported elevated serum levels of the peptide neurotensin (NT) in children with autism spectrum disorders (ASD). Here, we show that NT stimulates primary human microglia, the resident immune cells of the brain, and the immortalized cell line of human microglia-SV40. NT (10 nM) increases the gene expression and release (P < 0.001) of the proinflammatory cytokine IL-1β and chemokine (C-X-C motif) ligand 8 (CXCL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 from human microglia. NT also stimulates proliferation (P < 0.05) of microglia-SV40. Microglia express only the receptor 3 (NTR3)/sortilin and not the NTR1 or NTR2. The use of siRNA to target sortilin reduces (P < 0.001) the NT-stimulated cytokine and chemokine gene expression and release from human microglia. Stimulation with NT (10 nM) increases the gene expression of sortilin (P < 0.0001) and causes the receptor to be translocated from the cytoplasm to the cell surface, and to be secreted extracellularly. Our findings also show increased levels of sortilin (P < 0.0001) in the serum from children with ASD (n = 36), compared with healthy controls (n = 20). NT stimulation of microglia-SV40 causes activation of the mammalian target of rapamycin (mTOR) signaling kinase, as shown by phosphorylation of its substrates and inhibition of these responses by drugs that prevent mTOR activation. NT-stimulated responses are inhibited by the flavonoid methoxyluteolin (0.1–1 μM). The data provide a link between sortilin and the pathological findings of microglia and inflammation of the brain in ASD. Thus, inhibition of this pathway using methoxyluteolin could provide an effective treatment of ASD.

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“…These cells release cytokines as a response to viral damage, promoting cell death and aberrant neurogenesis by NPCs (Bayless, Greenberg, Swigut, Wysocka, & Blish, 2016), the process responsible for populating the brain with neurons (Götz & Huttner, 2005). One of the key pathways in neurogenesis is the PI3K-Akt-mTOR axis that induces cellular differentiation, migration, and maturation (Lee, 2015;Wahane et al, 2014). After exposure to the two nonstructural ZIKV proteins, NS4A and NS4B, the PI3K-Akt-mTOR pathway was strongly suppressed, leading to upregulation of the autophagy and impairment of neurogenesis in fetal NSC (Liang et al, 2016).…”

Section: Experimental Findings That Clarified Zikv Pathology In Thementioning

confidence: 99%

Zika infection and the development of neurological defects

Russo

Jungmann

Beltrão-Braga

2017

Cellular Microbiology

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SummaryStarting with the outbreak in Brazil, Zika virus (ZIKV) infection has been correlated with severe syndromes such as congenital Zika syndrome and Guillain-Barré syndrome. Here, we review the status of Zika virus pathogenesis in the central nervous system (CNS). One of the main concerns about ZIKV exposure during pregnancy is abnormal brain development, which results in microcephaly in newborns. Recent advances in in vitro research show that ZIKV can infect and obliterate cells from the CNS, such as progenitors, neurons, and glial cells. Neural progenitor cells seem to be the main target of the virus, with infection leading to less cell migration, neurogenesis impairment, cell death and, consequently, microcephaly in newborns. The downsizing of the brain can be directly associated with defective development of the cortical layer. In addition, in vivo investigations in mice reveal that ZIKV can cross the placenta and migrate to fetuses, but with a significant neurotropism, which results in brain damage for the pups. Another finding shows that hydrocephaly is an additional consequence of ZIKV infection, being detected during embryonic and fetal development in mouse, as well as after birth in humans. In spite of the advances in ZIKV research in the last year, the mechanisms underlying ZIKV infection in the CNS require further investigation particularly as there are currently no treatments or vaccines against ZIKV infection.

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Roles of mTOR Signaling in Brain Development

Cited by 117 publications

References 76 publications

Prenatal ethanol intoxication and maternal intubation stress alter cell survival and apoptosis in the postnatal development of rat hippocampus

Prenatal ethanol intoxication and maternal intubation stress alter cell survival and apoptosis in the postnatal development of rat hippocampus

Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism

Zika infection and the development of neurological defects

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