Deregulation of EIF4E: a novel mechanism for autism

Neves-Pereira, Maria; Müller, Berndt; Massie, D.; Williams, James H.; O’Brien, Patricia C.; Shen, Sanbing; Clair, David St; Miedzybrodzka, Zosia

doi:10.1136/jmg.2009.066852

Cited by 130 publications

(94 citation statements)

References 42 publications

(57 reference statements)

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“…Hypersensitivity to induction of mGluR-mediated LTD is implicated in the neurological deficits of fragile X and autism (Kelleher & Bear 2008), which is consistent with the observation that both fragile X and autism are associated with increased PI3K activity (Butler et al 2005;Cuscó et al 2009;Gross et al 2010;Jeon et al 2011;Kwon et al 2006;Mills et al 2007;Neves-Pereira et al 2009;Serajee et al 2003). Therefore there is interest in determining the mechanisms by which mGluR activation activates PI3K.…”

Section: A Role For Ras In Mammalian Metabotropic Glutamate Receptor-supporting

confidence: 68%

Ras‐dependent and Ras‐independent effects of PI3K in Drosophila motor neurons

Johnson

Lin

Stern

2012

Genes Brain and Behavior

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The lipid kinase PI3K plays key roles in cellular responses to activation of receptor tyrosine kinases or G protein coupled receptors such as the metabotropic glutamate receptor (mGluR). Activation of the PI3K catalytic subunit p110 occurs when the PI3K regulatory subunit p85 binds to phosphotyrosine residues present in upstream activating proteins. In addition, Ras is uniquely capable of activating PI3K in a p85-independent manner by binding to p110 at amino acids distinct from those recognized by p85. Because Ras, like p85, is activated by phosphotyrosines in upstream activators, it can be difficult to determine if particular PI3K-dependent processes require p85 or Ras. Here, we ask if PI3K requires Ras activity for either of two different PI3K-regulated processes within Drosophila larval motor neurons. To address this question, we determined the effects on each process of transgenes and chromosomal mutations that decrease Ras activity, or mutations that eliminate the ability of PI3K to respond to activated Ras. We found that PI3K requires Ras activity to decrease motor neuron excitability, an effect mediated by ligand activation of the single Drosophila mGluR DmGluRA. In contrast, the ability of PI3K to increase nerve terminal growth is Ras-independent. These results suggest that distinct regulatory mechanisms underlie the effects of PI3K on distinct phenotypic outputs.

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Section: A Role For Ras In Mammalian Metabotropic Glutamate Receptor-supporting

confidence: 68%

Ras‐dependent and Ras‐independent effects of PI3K in Drosophila motor neurons

Johnson

Lin

Stern

2012

Genes Brain and Behavior

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“…Recent evidence indicates that dysregulation and or mutations of FMRP-interacting proteins, such as the cytoplasmic FMRP-interacting protein 1 (CYFIP1) (52-55), eukaryotic initiation factor 4 (eIF4E) (56,57), and a subset of FMRP mRNA targets (58), may contribute to the ASD phenotype observed in FXS.…”

Section: Figurementioning

confidence: 99%

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

Bagni¹,

Tassone²,

Neri³

et al. 2012

J. Clin. Invest.

281

289

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Genetics of fragile XFragile X syndrome (FXS), an X-linked condition first described by Martin and Bell (1), is the leading cause of inherited intellectual disability (ID). Estimates report that FXS affects approximately 1 in 2,500 to 5,000 men and 1 in 4,000 to 6,000 women (2, 3). FXS is caused by mutations in the FMR1 gene, which is located on the X chromosome and whose locus at Xq27.3 coincides with the folate-sensitive fragile site (4, 5). Cytogenetic methods (6) used in the past to diagnose FXS have been replaced by molecular diagnostic of FMR1 DNA using Southern blot analysis and, more recently, PCR.Affected men display varying degrees of symptoms ranging from mild to severe. Due to compensation by the unaffected X chromosome, only one-third of female carriers with a full mutation (FM) have ID; the majority have normal IQ, although learning difficulties and emotional problems are common (7).Identified in 1991 by positional cloning (8), the FMR1 gene is characterized by the presence of a polymorphic CGG triplet sequence in the 5′ UTR (8, 9). Expansion in this triplet sequence gives rise to FXS, which is the prototype of unstable triplet expansion disorders. The triplet variability defines four types of alleles (Figure 1). Normal alleles have a number of CGG repeats, ranging from 5 to 54, with a mode of 30. Premutation (PM) alleles have a number of CGG repeats, ranging from 55 to 200. PM alleles are unstable and have a strong tendency to expand to FM alleles upon maternal transmission. Expansion from a PM to FM can occur with alleles as small as 56 CGGs (10). Alleles possessing between 45 and 54 CGG repeats, referred to as gray-zone or intermediate alleles, are proposed to be precursors of PM alleles, potentially due to paternal and maternal meiotic instability (11). The risk of a PM to FM transition depends on the CGG repeat size, such that the expansion risk is nearly 100% for alleles of >99 CGG repeats (11). A recent study (12) showed that the number of AGG interruptions present in the CGG repeats correlates inversely with the risk of expansion to a FM in the next generation. The presence of AGG interruptions, in addition to the CGG length, may thus better define the risk for transmission from a maternal PM to FM in the offspring.FMR1 silencing is the consequence of rather complex epigenetic modifications (13). In FXS, cytosines located approximately up to 1-kb upstream of the CGG repeat sequences, including the FMR1 promoter, are methylated (14, 15). Normal alleles are also methylated in the FMR1 promoter region but not in close proximity to the CGG repeat, which seems to be a "boundary" in the normal allele that prevents methylation from spreading. This boundary is missing in FM alleles, and the cytosines upstream of the CGG repeat become methylated around the thirteenth week of embryonic development (16). As a consequence, gene transcription is inhibited, leading to the absence of its protein product FMRP (17). Of note, some alleles remain partially or even fully unmethylated (UFM), despite containing ...

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“…Several of these OTR signal transducers are associated with both ASD and protein translation; mutations in PI3K, PTEN, and tuberosclerosis protein (TSC2), members of the Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway that control ribosomal protein and translation factor activity have been linked with ASD (Kelleher and Bear 2008). Further support for aberrant protein translation in ASD comes from the finding of mutations in a negative regulator of mRNA translation for fragile X mental retardation protein 1 (FMRP1), as well as mutations in the eukaryotic translation factor 4E (eIF4E), both of which are linked to autism (Kelleher and Bear 2008;Neves-Pereira et al 2009;Gkogkas et al 2013;Wang and Doering 2013). It is therefore highly probable that OT may regulate protein translation in neuronal circuits important to normal social behaviors and, in enterocytes essential for normal gut development and/or function.…”

Section: Introductionmentioning

confidence: 99%

Oxytocin modulates markers of the unfolded protein response in Caco2BB gut cells

Klein

Tamir

Hirschberg

et al. 2014

Cell Stress and Chaperones

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We have shown that oxytocin receptor (OTR) expression in neonatal rat enterocytes is robust from birth to weaning, but OTR function during this period is unknown. We previously reported that oxytocin (OT) stimulation of Caco2BB cells (enterocytes in vitro) inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling. The unfolded protein response (UPR) is known to protectively reduce translation during endoplasmic reticulum (ER) stress. Because the mTORC1 pathway is linked to cellular stress, we investigated markers of UPR in OT-stimulated Caco2BB cells. We report that OT modulates several factors involved in sensing and translation of ER stress. High OT (62.5 nM) reduced translation initiation factor 4E-BP1 phosphorylation (Ser65), which is known to inhibit cap-dependent translation via its rate-limiting eukaryotic translation initiation factor 4E (eIF4E). Importantly, high OT increased phosphorylation of eukaryotic translation initiation factor 2a (eIF2a) phosphoSer51, which inhibits eIF2a. High OT also increased protein kinase RNA-like endoplasmic reticulum kinase phosphorylation, a sensor of ER stress and a kinase of eIF2a. Both high and low OT activated inositol requiring enzyme1 (IRE1), which generates the transcription factor X-box binding protein 1 (XBP1) and induces the UPR. We also show that OT modulates XBP1 splicing and induces tribbles 3 (TRIB3; a negative regulator of Akt and protein involved in autophagy) and immunoglobulin binding protein (BiP; ER-chaperone). Taken together, these results indicate that OT modulates sensors of ER stress and autophagy. These findings support our hypothesis that transiently elevated OTR expression in neonatal gut may serve a protective function during a critical postnatal developmental period.

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Deregulation of EIF4E: a novel mechanism for autism

Cited by 130 publications

References 42 publications

Ras‐dependent and Ras‐independent effects of PI3K in Drosophila motor neurons

Ras‐dependent and Ras‐independent effects of PI3K in Drosophila motor neurons

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

Oxytocin modulates markers of the unfolded protein response in Caco2BB gut cells

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