title: Rheb activation in subventricular zone progenitors leads to heterotopia, ectopic neuronal differentiation, and rapamycin-sensitive olfactory micronodules and dendrite hypertrophy of newborn neurons.
abstract: Mammalian target of rapamycin (mTOR) hyperactivity in perinatal neural progenitor cells (NPCs) of tuberous sclerosis complex 1 (Tsc1) heterozygote mice leads to heterotopia and abnormal neuronal morphogenesis as seen in patients with tuberous sclerosis. Considering that pathological hyperactive mTOR also occurs in individuals carrying no genetic mutations, we examined whether increasing mTOR activity in neonatal NPCs of wild-type mice would recapitulate the above phenotypes. Electroporation of a plasmid encoding constitutively active Ras-homolog enriched in brain (Rheb(CA)) into subventricular zone NPCs increased mTOR activity in newborn cells. At 19 d post-electroporation (dpe), heterotopia and ectopic cells with a neuronal morphology were observed along the migratory path [rostral migratory stream (RMS)] and in the olfactory bulb (OB). These ectopic cells displayed action potentials and received synaptic inputs identifying them as synaptically integrated neurons. RMS heterotopias contained astrocytes, neurons, and entrapped neuroblasts. Immunostaining at 3 dpe revealed the presence of Mash1(+) Olig2(-) cells in the migratory route accompanied by ectopic neuronal differentiation and altered direction and speed of neuroblast migration at 7 dpe, suggesting a non-cell-autonomous disruption of migration. At >19 dpe, newborn Rheb(CA)-expressing neurons displayed altered distribution and formed micronodules in the OB. In addition, they displayed increased dendritic complexity along with altered membrane biophysics and increased frequency of GABAergic synaptic inputs. OB heterotopia, micronodules, and dendrite hypertrophy were notably prevented by rapamycin treatment, suggesting their mTOR dependence. Collectively, these data show that increasing mTOR activity in neonatal NPCs of wild-type mice recapitulate the pathologies observed in Tsc1 mutant mice. In addition, increased mTOR activity in individuals without known mutations could significantly impact neurogenesis and circuit formation.
authors: Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors: Carlos A
authors: CA
authors: Lafourcade
authors: Tiffany V
authors: TV
authors: Lin
authors: David M
authors: DM
authors: Feliciano
authors: Longbo
authors: L
authors: Zhang
authors: Lawrence S
authors: LS
authors: Hsieh
authors: Angélique
authors: A
authors: Bordey
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049108:Cell Enlargement / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002552:Cerebral Ventricles / Q000378:metabolism / Q000473:pathology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018274:Electroporation / Q000379:methods; D005260:Female; D006984:Hypertrophy / Q000473:pathology; D008297:Male; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism* / Q000502:physiology; D009830:Olfactory Bulb / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000076205:Ras Homolog Enriched in Brain Protein; D020123:Sirolimus / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins; D020123:Sirolimus
references: Hum Mol Genet. 2012 Feb 15;21(4):799-810
references: 22068588
references: Nat Neurosci. 2011 Aug 30;14(11):1481-8
references: 21878933
references: PLoS One. 2012;7(5):e38174
references: 22693596
references: Cereb Cortex. 2010 Nov;20(11):2583-91
references: 20154014
references: Biochim Biophys Acta. 2008 Jan;1784(1):116-32
references: 17913600
references: J Clin Invest. 2011 Apr;121(4):1596-607
references: 21403402
references: Nat Neurosci. 2010 Feb;13(2):163-72
references: 20062052
references: EMBO J. 2004 Nov 10;23(22):4495-505
references: 15496983
references: Cell Host Microbe. 2008 Apr 17;3(4):253-62
references: 18407068
references: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3514-9
references: 17360675
references: Nat Genet. 2005 Jan;37(1):19-24
references: 15624019
references: J Clin Invest. 2010 May;120(5):1591-602
references: 20424326
references: N Engl J Med. 2006 Sep 28;355(13):1345-56
references: 17005952
references: Brain Dev. 2001 Nov;23(7):508-15
references: 11701246
references: Genes Dev. 2004 Mar 15;18(6):660-72
references: 15075293
references: Nat Rev Mol Cell Biol. 2009 May;10(5):307-18
references: 19339977
references: Cell Cycle. 2011 Oct 15;10(20):3452-60
references: 22067656
references: J Comp Neurol. 2004 Aug 23;476(3):290-300
references: 15269971
references: Genes Brain Behav. 2012 Apr;11(3):332-41
references: 22268788
references: J Biol Chem. 2008 Dec 12;283(50):35053-9
references: 18948269
references: Cell Stem Cell. 2011 Nov 4;9(5):447-62
references: 22056141
references: Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R251-8
references: 16244323
references: Nat Methods. 2012 Jun 28;9(7):676-82
references: 22743772
references: J Neurophysiol. 2003 Oct;90(4):2291-302
references: 12801891
references: Curr Opin Neurobiol. 2009 Apr;19(2):231-4
references: 19545994
references: Glia. 2006 Sep;54(4):329-42
references: 16862532
references: Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):E1070-9
references: 22025691
references: J Neurobiol. 2002 Sep 5;52(3):251-65
references: 12210108
references: Neuron. 1993 Feb;10(2):201-12
references: 8439409
references: J Virol. 2005 May;79(9):5499-506
references: 15827164
references: Development. 2012 Sep;139(18):3422-31
references: 22874917
references: Front Neurosci. 2010 Jul 19;4:
references: 20700392
references: Hum Mol Genet. 2011 Feb 1;20(3):445-54
references: 21062901
references: Neural Dev. 2011 Apr 05;6:12
references: 21466690
references: Dev Biol. 1999 Dec 15;216(2):622-34
references: 10642797
references: Oncogene. 2008 Sep 18;27(41):5416-30
references: 18794877
references: Neuron. 2010 Mar 25;65(6):859-72
references: 20346761
references: J Neurosci. 2007 May 23;27(21):5546-58
references: 17522300
references: J Neurosci. 2004 Sep 1;24(35):7623-31
references: 15342728
references: Expert Rev Anticancer Ther. 2011 Aug;11(8):1181-92
references: 21916571
references: J Neurosci. 2004 Nov 17;24(46):10530-41
references: 15548668
references: Nat Neurosci. 2009 Dec;12(12):1524-33
references: 19881504
references: Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35
references: 21157483
references: Neuron. 2006 May 4;50(3):377-88
references: 16675393
references: Epilepsia. 2009 Jan;50(1):147-54
references: 19125835
references: Trends Neurosci. 2010 Feb;33(2):67-75
references: 19963289
references: Neuropharmacology. 2010 May;58(6):865-76
references: 20097213
references: Hum Mol Genet. 2009 Apr 1;18(7):1252-65
references: 19150975
references: Brain. 2007 Sep;130(Pt 9):2267-76
references: 17711980