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Cited by 37Genetics and Neurodevelopmental DisordersTuberous Sclerosis Complex ResearchPI3K/AKT/mTOR signaling in cancer

The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function

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Nguyen, Lena H, Xu, Youfen, Nair, Maanasi, Bordey, Angelique·2024·eLife
DOI 10.7554/elife.91010PMC PMC10942629

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Abstract

Brain somatic mutations in various components of the mTOR complex 1 (mTORC1) pathway have emerged as major causes of focal malformations of cortical development and intractable epilepsy. While these distinct gene mutations converge on excessive mTORC1 signaling and lead to common clinical manifestations, it remains unclear whether they cause similar cellular and synaptic disruptions underlying cortical network hyperexcitability. Here, we show that in utero activation of the mTORC1 activator genes, Rheb or MTOR , or biallelic inactivation of the mTORC1 repressor genes, Depdc5 , Tsc1 , or Pten in the mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability but different changes in excitatory synaptic transmission. Our findings suggest that, despite converging on mTORC1 signaling, mutations in different mTORC1 pathway genes differentially impact cortical excitatory synaptic activity, which may confer gene-specific mechanisms of hyperexcitability and responses to therapeutic intervention.

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  • These mutations contribute to mesolimbic, cerebellar, and cortical dysplasia, hamartomas, tumor susceptibility, and a high prevalence of ASD.

    “These mutations contribute to mesolimbic, cerebellar, and cortical dysplasia, hamartomas, tumor susceptibility, and a high prevalence of ASD (Nguyen et al., 2024).”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Nguyen et al., 2024

    The Introduction (page not provided) says somatic mutations in mTORC1-pathway regulators are genetic causes of focal cortical dysplasia and hemimegalencephaly. Our copy does not support the additional claims about mesolimbic or cerebellar dysplasia, hamartomas, tumor susceptibility, or a high prevalence of ASD. (LLM, conf=0.87)

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Research works printed but not linked: 71

  1. Bar-Peled L Sabatini DM 2014 Regulation of mTORC1 by amino acids Trends in Cell Biology 24 400 406 10.1016/j.tcb.2014.03.003 24698685 PMC4074565 · DOI · Paper page
  2. Blumcke I Spreafico R Haaker G Coras R Kobow K Bien CG Pfäfflin M Elger C Widman G Schramm J Becker A Braun KP Leijten F Baayen JC Aronica E Chassoux F Hamer H Stefan H Rössler K Thom M Walker MC Sisodiya SM Duncan JS McEvoy AW Pieper T Holthausen H Kudernatsch M Meencke HJ Kahane P Schulze-Bonhage A Zentner J Heiland DH Urbach H Steinhoff BJ Bast T Tassi L Lo Russo G Özkara C Oz B Krsek P Vogelgesang S Runge U Lerche H Weber Y Honavar M Pimentel J Arzimanoglou A Ulate-Campos A Noachtar S Hartl E Schijns O Guerrini R Barba C Jacques TS Cross JH Feucht M Mühlebner A Grunwald T Trinka E Winkler PA Gil-Nagel A Toledano Delgado R Mayer T Lutz M Zountsas B Garganis K Rosenow F Hermsen A von Oertzen TJ Diepgen TL Avanzini G EEBB Consortium 2017 Histopathological findings in brain tissue obtained during epilepsy surgery The New England Journal of Medicine 377 1648 1656 10.1056/NEJMoa1703784 29069555 · DOI
  3. Breunig JJ Gate D Levy R Rodriguez J Kim GB Danielpour M Svendsen CN Town T 2012 Rapid genetic targeting of pial surface neural progenitors and immature neurons by neonatal electroporation Neural Development 7 26 10.1186/1749-8104-7-26 22776033 PMC3479020 · DOI
  4. Calcagnotto ME Paredes MF Tihan T Barbaro NM Baraban SC 2005 Dysfunction of synaptic inhibition in epilepsy associated with focal cortical dysplasia The Journal of Neuroscience 25 9649 9657 10.1523/JNEUROSCI.2687-05.2005 16237169 PMC6725719 · DOI
  5. Cepeda C Hurst RS Flores-Hernández J Hernández-Echeagaray E Klapstein GJ Boylan MK Calvert CR Jocoy EL Nguyen OK André VM Vinters HV Ariano MA Levine MS Mathern GW 2003 Morphological and electrophysiological characterization of abnormal cell types in pediatric cortical dysplasia Journal of Neuroscience Research 72 472 486 10.1002/jnr.10604 12704809 · DOI
  6. Cepeda C André VM Vinters HV Levine MS Mathern GW 2005 Are cytomegalic neurons and balloon cells generators of epileptic activity in pediatric cortical dysplasia? Epilepsia 46 82 88 10.1111/j.1528-1167.2005.01013.x 15987258 · DOI
  7. Cepeda C André VM Yamazaki I Hauptman JS Chen JY Vinters HV Mathern GW Levine MS 2010 Comparative study of cellular and synaptic abnormalities in brain tissue samples from pediatric tuberous sclerosis complex and cortical dysplasia type II Epilepsia 51 160 165 10.1111/j.1528-1167.2010.02633.x 20618424 PMC2909023 · DOI
  8. Chen F Rosiene J Che A Becker A LoTurco J 2015 Tracking and transforming neocortical progenitors by CRISPR/Cas9 gene targeting and piggyBac transposase lineage labeling Development 142 3601 3611 10.1242/dev.118836 26400094 PMC4631763 · DOI
  9. Chen CJ Sgritta M Mays J Zhou H Lucero R Park J Wang IC Park JH Kaipparettu BA Stoica L Jafar-Nejad P Rigo F Chin J Noebels JL Costa-Mattioli M 2019 Therapeutic inhibition of mTORC2 rescues the behavioral and neurophysiological abnormalities associated with Pten-deficiency Nature Medicine 25 1684 1690 10.1038/s41591-019-0608-y 31636454 PMC7082835 · DOI
  10. Chetram MA Hinton CV 2012 PTEN regulation of ERK1/2 signaling in cancer Journal of Receptor and Signal Transduction Research 32 190 195 10.3109/10799893.2012.695798 22737980 PMC3503241 · DOI
  11. Chung C Yang X Bae T Vong KI Mittal S Donkels C Westley Phillips H Li Z Marsh APL Breuss MW Ball LL Garcia CAB George RD Gu J Xu M Barrows C James KN Stanley V Nidhiry AS Khoury S Howe G Riley E Xu X Copeland B Wang Y Kim SH Kang HC Schulze-Bonhage A Haas CA Urbach H Prinz M Limbrick DD Gurnett CA Smyth MD Sattar S Nespeca M Gonda DD Imai K Takahashi Y Chen HH Tsai JW Conti V Guerrini R Devinsky O Silva WA Machado HR Mathern GW Abyzov A Baldassari S Baulac S Gleeson JG Focal Cortical Dysplasia Neurogenetics Consortium Brain Somatic Mosaicism Network 2023 Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development Nature Genetics 55 209 220 10.1038/s41588-022-01276-9 36635388 PMC9961399 · DOI
  12. Crino PB 2009 Focal brain malformations: seizures, signaling, sequencing Epilepsia 50 3 8 10.1111/j.1528-1167.2009.02289.x 19761448 · DOI
  13. Cullen ER Tariq K Shore AN Luikart BW Weston MC 2023 mTORC2 inhibition improves morphological effects of PTEN loss, but does not correct synaptic dysfunction or prevent seizures The Journal of Neuroscience 43 827 845 10.1523/JNEUROSCI.1354-22.2022 36526374 PMC9899090 · DOI
  14. Cullen ER Safari M Mittelstadt I Weston MC 2024 Hyperactivity of mTORC1 and mTORC2-Dependent Signaling Mediate Epilepsy Downstream of Somatic PTEN Loss bioRxiv 10.1101/2023.08.18.553856 PMC10942640 38446016 · DOI
  15. D’Gama AM Woodworth MB Hossain AA Bizzotto S Hatem NE LaCoursiere CM Najm I Ying Z Yang E Barkovich AJ Kwiatkowski DJ Vinters HV Madsen JR Mathern GW Blümcke I Poduri A Walsh CA 2017 somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias Cell Reports 21 3754 3766 10.1016/j.celrep.2017.11.106 29281825 PMC5752134 · DOI
  16. Dibble CC Cantley LC 2015 Regulation of mTORC1 by PI3K signaling Trends in Cell Biology 25 545 555 10.1016/j.tcb.2015.06.002 26159692 PMC4734635 · DOI
  17. Doan TN Kunze DL 1999 Contribution of the hyperpolarization-activated current to the resting membrane potential of rat nodose sensory neurons The Journal of Physiology 514 125 138 10.1111/j.1469-7793.1999.125af.x 9831721 PMC2269051 · DOI
  18. Funahashi M Mitoh Y Kohjitani A Matsuo R 2003 Role of the hyperpolarization-activated cation current (Ih) in pacemaker activity in area postrema neurons of rat brain slices The Journal of Physiology 552 135 148 10.1113/jphysiol.2003.047191 12897173 PMC2343317 · DOI
  19. Gerasimenko A Baldassari S Baulac S 2023 mTOR pathway: Insights into an established pathway for brain mosaicism in epilepsy Neurobiology of Disease 182 106144 10.1016/j.nbd.2023.106144 37149062 · DOI
  20. Getz SA DeSpenza T Li M Luikart BW 2016 Rapamycin prevents, but does not reverse, aberrant migration in Pten knockout neurons Neurobiology of Disease 93 12 20 10.1016/j.nbd.2016.03.010 26992888 PMC5409093 · DOI
  21. Goz RU Akgül G LoTurco JJ 2020 BRAFV600E expression in neural progenitors results in a hyperexcitable phenotype in neocortical pyramidal neurons Journal of Neurophysiology 123 2449 2464 10.1152/jn.00523.2019 32401131 PMC7311733 · DOI
  22. Guerrini R Dobyns WB 2014 Malformations of cortical development: clinical features and genetic causes The Lancet. Neurology 13 710 726 10.1016/S1474-4422(14)70040-7 24932993 PMC5548104 · DOI · Paper page
  23. Harvey AS Cross JH Shinnar S Mathern GW ILAE Pediatric Epilepsy Surgery Survey Taskforce 2008 Defining the spectrum of international practice in pediatric epilepsy surgery patients Epilepsia 49 146 155 10.1111/j.1528-1167.2007.01421.x 18042232 · DOI
  24. Hsieh LS Wen JH Claycomb K Huang Y Harrsch FA Naegele JR Hyder F Buchanan GF Bordey A 2016 Convulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement Nature Communications 7 11753 10.1038/ncomms11753 27249187 PMC4895394 · DOI
  25. Hsieh LS Wen JH Nguyen LH Zhang L Getz SA Torres-Reveron J Wang Y Spencer DD Bordey A 2020 Ectopic HCN4 expression drives mTOR-dependent epilepsy in mice Science Translational Medicine 12 eabc1492 10.1126/scitranslmed.abc1492 33208499 PMC9888000 · DOI
  26. Hu S Knowlton RC Watson BO Glanowska KM Murphy GG Parent JM Wang Y 2018 Somatic Depdc5 deletion recapitulates electroclinical features of human focal cortical dysplasia type IIA Annals of Neurology 84 140 146 10.1002/ana.25272 30080265 PMC6119494 · DOI
  27. Huang J Dibble CC Matsuzaki M Manning BD 2008 The TSC1-TSC2 complex is required for proper activation of mTOR complex 2 Molecular and Cellular Biology 28 4104 4115 10.1128/MCB.00289-08 18411301 PMC2423120 · DOI
  28. Karalis V Caval-Holme F Bateup HS 2022 Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex Nature Communications 13 4665 10.1038/s41467-022-31961-6 35945201 PMC9363483 · DOI · Paper page
  29. Kase D Imoto K 2012 The Role of HCN channels on membrane excitability in the nervous system Journal of Signal Transduction 2012 619747 10.1155/2012/619747 22934165 PMC3425855 · DOI
  30. Koh HY Jang J Ju SH Kim R Cho GB Kim DS Sohn JW Paik SB Lee JH 2021 Non-cell autonomous epileptogenesis in focal cortical Dysplasia Annals of Neurology 90 285 299 10.1002/ana.26149 34180075 · DOI
  31. Kroon T van Hugte E van Linge L Mansvelder HD Meredith RM 2019 Early postnatal development of pyramidal neurons across layers of the mouse medial prefrontal cortex Scientific Reports 9 5037 10.1038/s41598-019-41661-9 30911152 PMC6433913 · DOI · Paper page
  32. Lamas JA 1998 A hyperpolarization-activated cation current (Ih) contributes to resting membrane potential in rat superior cervical sympathetic neurones Pflugers Archiv 436 429 435 10.1007/s004240050653 9644226 · DOI
  33. Laplante M Sabatini DM 2012 mTOR signaling in growth control and disease Cell 149 274 293 10.1016/j.cell.2012.03.017 22500797 PMC3331679 · DOI · Paper page
  34. Lee DF Kuo HP Chen CT Wei Y Chou CK Hung JY Yen CJ Hung MC 2008 IKKbeta suppression of TSC1 function links the mTOR pathway with insulin resistance International Journal of Molecular Medicine 22 633 638 10.3892/ijmm_00000065 18949383 PMC2586899 · DOI
  35. Lee WS Baldassari S Chipaux M Adle-Biassette H Stephenson SEM Maixner W Harvey AS Lockhart PJ Baulac S Leventer RJ 2021 Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia Annals of Clinical and Translational Neurology 8 485 490 10.1002/acn3.51286 33434304 PMC7886042 · DOI
  36. Li H Zhang P Zhang Q 2018 wwp2 is a physiological ubiquitin ligase for phosphatase and tensin homolog (pten) in mice Journal of Biological Chemistry 293 8886 8899 10.1074/jbc.RA117.001060 29685889 PMC5995496 · DOI
  37. Lien EC Dibble CC Toker A 2017 PI3K signaling in cancer: beyond AKT Current Opinion in Cell Biology 45 62 71 10.1016/j.ceb.2017.02.007 28343126 PMC5482768 · DOI
  38. Lim JS Kim W Kang HC Kim SH Park AH Park EK Cho YW Kim S Kim HM Kim JA Kim J Rhee H Kang SG Kim HD Kim D Kim DS Lee JH 2015 Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy Nature Medicine 21 395 400 10.1038/nm.3824 25799227 · DOI
  39. Lim JS Gopalappa R Kim SH Ramakrishna S Lee M Kim WI Kim J Park SM Lee J Oh JH Kim HD Park CH Lee JS Kim S Kim DS Han JM Kang HC Kim HH Lee JH 2017 Somatic mutations in TSC1 and TSC2 cause focal cortical Dysplasia American Journal of Human Genetics 100 454 472 10.1016/j.ajhg.2017.01.030 28215400 PMC5339289 · DOI
  40. Lin TV Hsieh L Kimura T Malone TJ Bordey A 2016 Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration PNAS 113 11330 11335 10.1073/pnas.1605740113 27647922 PMC5056085 · DOI
  41. Lohmann C Kessels HW 2014 The developmental stages of synaptic plasticity The Journal of Physiology 592 13 31 10.1113/jphysiol.2012.235119 24144877 PMC3903349 · DOI
  42. Lupica CR Bell JA Hoffman AF Watson PL 2001 Contribution of the hyperpolarization-activated current (I(h)) to membrane potential and GABA release in hippocampal interneurons Journal of Neurophysiology 86 261 268 10.1152/jn.2001.86.1.261 11431507 · DOI
  43. Manning BD Toker A 2017 AKT/PKB signaling: navigating the network Cell 169 381 405 10.1016/j.cell.2017.04.001 28431241 PMC5546324 · DOI · Paper page
  44. Marsan E Baulac S 2018 Review: Mechanistic target of rapamycin (mTOR) pathway, focal cortical dysplasia and epilepsy Neuropathology and Applied Neurobiology 44 6 17 10.1111/nan.12463 29359340 · DOI
  45. Mathern GW Cepeda C Hurst RS Flores-Hernandez J Mendoza D Levine MS 2000 Neurons recorded from pediatric epilepsy surgery patients with cortical dysplasia Epilepsia 41 S162 S167 10.1111/j.1528-1157.2000.tb01575.x 10999538 · DOI
  46. Mirzaa GM Campbell CD Solovieff N Goold C Jansen LA Menon S Timms AE Conti V Biag JD Adams C Boyle EA Collins S Ishak G Poliachik S Girisha KM Yeung KS Chung BHY Rahikkala E Gunter SA McDaniel SS Macmurdo CF Bernstein JA Martin B Leary R Mahan S Liu S Weaver M Doerschner M Jhangiani S Muzny DM Boerwinkle E Gibbs RA Lupski JR Shendure J Saneto RP Novotny EJ Wilson CJ Sellers WR Morrissey M Hevner RF Ojemann JG Guerrini R Murphy LO Winckler W Dobyns WB 2016 Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism JAMA Neurology 73 836 845 10.1001/jamaneurol.2016.0363 27159400 PMC4979321 · DOI
  47. Moen EL Fricano-Kugler CJ Luikart BW O’Malley AJ 2016 Analyzing clustered data: why and how to account for multiple observations nested within a study participant? PLOS ONE 11 e0146721 10.1371/journal.pone.0146721 26766425 PMC4713068 · DOI
  48. Møller RS Weckhuysen S Chipaux M Marsan E Taly V Bebin EM Hiatt SM Prokop JW Bowling KM Mei D Conti V de la Grange P Ferrand-Sorbets S Dorfmüller G Lambrecq V Larsen LHG Leguern E Guerrini R Rubboli G Cooper GM Baulac S 2016 Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy Neurology. Genetics 2 e118 10.1212/NXG.0000000000000118 27830187 PMC5089441 · DOI
  49. Mühlebner A Bongaarts A Sarnat HB Scholl T Aronica E 2019 New insights into a spectrum of developmental malformations related to mTOR dysregulations: challenges and perspectives Journal of Anatomy 235 521 542 10.1111/joa.12956 30901081 PMC6704243 · DOI
  50. Nakashima M Saitsu H Takei N Tohyama J Kato M Kitaura H Shiina M Shirozu H Masuda H Watanabe K Ohba C Tsurusaki Y Miyake N Zheng Y Sato T Takebayashi H Ogata K Kameyama S Kakita A Matsumoto N 2015 Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb Annals of Neurology 78 375 386 10.1002/ana.24444 26018084 · DOI
  51. Neuman NA Henske EP 2011 Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis EMBO Molecular Medicine 3 189 200 10.1002/emmm.201100131 21412983 PMC3377068 · DOI
  52. Nguyen LH Brewster AL Clark ME Regnier-Golanov A Sunnen CN Patil VV D’Arcangelo G Anderson AE 2015 mTOR inhibition suppresses established epilepsy in a mouse model of cortical dysplasia Epilepsia 56 636 646 10.1111/epi.12946 25752454 PMC4459784 · DOI
  53. Nguyen LH Mahadeo T Bordey A 2019 mTOR hyperactivity levels influence the severity of epilepsy and associated neuropathology in an experimental model of tuberous sclerosis complex and focal cortical Dysplasia The Journal of Neuroscience 39 2762 2773 10.1523/JNEUROSCI.2260-18.2019 30700531 PMC6445990 · DOI
  54. Nguyen LH Bordey A 2021 Convergent and divergent mechanisms of epileptogenesis in mTORopathies Frontiers in Neuroanatomy 15 664695 10.3389/fnana.2021.664695 33897381 PMC8064518 · DOI
  55. Nguyen LH Bordey A 2022 Current review in basic science: Animal models of focal cortical dysplasia and epilepsy Epilepsy Currents 22 234 240 10.1177/15357597221098230 36187145 PMC9483763 · DOI
  56. Nguyen LH Xu Y Mahadeo T Zhang L Lin TV Born HA Anderson AE Bordey A 2022 Expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy Brain 145 1310 1325 10.1093/brain/awab390 34849602 PMC9128821 · DOI
  57. Okoh J Mays J Bacq A Oses-Prieto JA Tyanova S Chen CJ Imanbeyev K Doladilhe M Zhou H Jafar-Nejad P Burlingame A Noebels J Baulac S Costa-Mattioli M 2023 Targeted suppression of mTORC2 reduces seizures across models of epilepsy Nature Communications 14 7364 10.1038/s41467-023-42922-y 37963879 PMC10645975 · DOI
  58. Proietti Onori M Koene LMC Schäfer CB Nellist M de Brito van Velze M Gao Z Elgersma Y van Woerden GM 2021 RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity PLOS Biology 19 e3001279 10.1371/journal.pbio.3001279 34038402 PMC8186814 · DOI
  59. Sacco JJ Yau TY Darling S Patel V Liu H Urbé S Clague MJ Coulson JM 2014 The deubiquitylase Ataxin-3 restricts PTEN transcription in lung cancer cells Oncogene 33 4265 4272 10.1038/onc.2013.512 24292675 PMC4351423 · DOI
  60. Swaminathan A Hassan-Abdi R Renault S Siekierska A Riché R Liao M de Witte PAM Yanicostas C Soussi-Yanicostas N Drapeau P Samarut É 2018 Non-canonical mTOR-Independent Role of DEPDC5 in Regulating GABAergic network development Current Biology 28 1924 1937 10.1016/j.cub.2018.04.061 29861134 · DOI
  61. Tae HS Smith KM Phillips AM Boyle KA Li M Forster IC Hatch RJ Richardson R Hughes DI Graham BA Petrou S Reid CA 2017 Gabapentin modulates HCN4 channel voltage-dependence Frontiers in Pharmacology 8 554 10.3389/fphar.2017.00554 28871229 PMC5566583 · DOI
  62. Thoby-Brisson M Telgkamp P Ramirez JM 2000 The role of the hyperpolarization-activated current in modulating rhythmic activity in the isolated respiratory network of mice The Journal of Neuroscience 20 2994 3005 10.1523/JNEUROSCI.20-08-02994.2000 10751452 PMC6772196 · DOI
  63. Vazquez F Ramaswamy S Nakamura N Sellers WR 2000 Phosphorylation of the PTEN tail regulates protein stability and function Molecular and Cellular Biology 20 5010 5018 10.1128/MCB.20.14.5010-5018.2000 10866658 PMC85951 · DOI
  64. Wong CW Or PMY Wang Y Li L Li J Yan M Cao Y Luk HM Tong TMF Leslie NR Lo IFM Choy KW Chan AML 2018 Identification of a PTEN mutation with reduced protein stability, phosphatase activity, and nuclear localization in Hong Kong patients with autistic features, neurodevelopmental delays, and macrocephaly Autism Research 11 1098 1109 10.1002/aur.1950 29608813 PMC6220804 · DOI
  65. Wu X Sosunov AA Lado W Teoh JJ Ham A Li H Al-Dalahmah O Gill BJA Arancio O Schevon CA Frankel WN McKhann GM Sulzer D Goldman JE Tang G 2022 Synaptic hyperexcitability of cytomegalic pyramidal neurons contributes to epileptogenesis in tuberous sclerosis complex Cell Reports 40 111085 10.1016/j.celrep.2022.111085 35858542 PMC9376014 · DOI
  66. Xue W Chen S Yin H Tammela T Papagiannakopoulos T Joshi NS Cai W Yang G Bronson R Crowley DG Zhang F Anderson DG Sharp PA Jacks T 2014 CRISPR-mediated direct mutation of cancer genes in the mouse liver Nature 514 380 384 10.1038/nature13589 25119044 PMC4199937 · DOI · Paper page
  67. Yang Y Zhou F Fang Z Wang L Li Z Sun L Wang C Yao W Cai X Jin J Zha X 2009 Post-transcriptional and post-translational regulation of PTEN by transforming growth factor-beta1 Journal of Cellular Biochemistry 106 1102 1112 10.1002/jcb.22100 19206163 · DOI
  68. Yim EK Peng G Dai H Hu R Li K Lu Y Mills GB Meric-Bernstam F Hennessy BT Craven RJ Lin SY 2009 Rak functions as a tumor suppressor by regulating PTEN protein stability and function Cancer Cell 15 304 314 10.1016/j.ccr.2009.02.012 19345329 PMC2673492 · DOI
  69. Yu Z Guindani M Grieco SF Chen L Holmes TC Xu X 2022 Beyond t test and ANOVA: applications of mixed-effects models for more rigorous statistical analysis in neuroscience research Neuron 110 21 35 10.1016/j.neuron.2021.10.030 34784504 PMC8763600 · DOI · Paper page
  70. Yuskaitis CJ Jones BM Wolfson RL Super CE Dhamne SC Rotenberg A Sabatini DM Sahin M Poduri A 2018 A mouse model of DEPDC5-related epilepsy: Neuronal loss of DEPDC5 causes dysplastic and ectopic neurons, increased mTOR signaling, and seizure susceptibility Neurobiology of Disease 111 91 101 10.1016/j.nbd.2017.12.010 29274432 PMC5803417 · DOI
  71. Zhao S Li Z Zhang M Zhang L Zheng H Ning J Wang Y Wang F Zhang X Gan H Wang Y Zhang X Luo H Bu G Xu H Yao Y Zhang YW 2019 A brain somatic RHEB doublet mutation causes focal cortical dysplasia type II Experimental & Molecular Medicine 51 1 11 10.1038/s12276-019-0277-4 31337748 PMC6802736 · DOI

Cited by

Sorted by citations

Authors
Nguyen, L. H., Xu, Y., Nair, M., & Bordey, A.
Affiliations
  • The University of Texas at Dallas (US)
  • Departments of Neurosurgery and Cellular & Molecular Physiology, Wu Tsai Institute, Yale University School of Medicine
Corresponding author
Nguyen, Lena H
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-02-27
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.91010
PMC
PMC10942629
OpenAlex
W4387542144
Cited by
37
References
7
Citations by year
2026: 11 · 2025: 14 · 2024: 12
FWCI
6.14
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (F32 HD095567, R01 NS111980)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
mTORC1 signaling, mTOR, Rheb, DEPDC5, PTEN, TSC1, drug-resistant epilepsy, cortical hyperexcitability, excitatory synaptic transmission, medial prefrontal cortex, somatic mutations, synaptic excitability
MeSH terms
Drug Resistant Epilepsy, Mechanistic Target of Rapamycin Complex 1, Animals, Brain, Neurons, Pyramidal Cells, Mice

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