title: Inactivation of mTORC1 in the developing brain causes microcephaly and affects gliogenesis.
abstract: The mammalian target of rapamycin (mTOR) regulates cell growth in response to various intracellular and extracellular signals. It assembles into two multiprotein complexes: the rapamycin-sensitive mTOR complex 1 (mTORC1) and the rapamycin-insensitive mTORC2. In this study, we inactivated mTORC1 in mice by deleting the gene encoding raptor in the progenitors of the developing CNS. Mice are born but never feed and die within a few hours. The brains deficient for raptor show a microcephaly starting at E17.5 that is the consequence of a reduced cell number and cell size. Changes in cell cycle length during late cortical development and increased cell death both contribute to the reduction in cell number. Neurospheres derived from raptor-deficient brains are smaller, and differentiation of neural progenitors into glia but not into neurons is inhibited. The differentiation defect is paralleled by decreased Stat3 signaling, which is a target of mTORC1 and has been implicated in gliogenesis. Together, our results show that postnatal survival, overall brain growth, and specific aspects of brain development critically depend on mTORC1 function.
authors: Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
authors: Dimitri
authors: D
authors: Cloëtta
authors: Venus
authors: V
authors: Thomanetz
authors: Constanze
authors: C
authors: Baranek
authors: Regula M
authors: RM
authors: Lustenberger
authors: Shuo
authors: S
authors: Lin
authors: Filippo
authors: F
authors: Oliveri
authors: Suzana
authors: S
authors: Atanasoski
authors: Markus A
authors: MA
authors: Rüegg
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D009457:Neuroglia / Q000473:pathology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D011506:Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014157:Transcription Factors; D014404:Tubulin; C462941:beta3 tubulin, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3; D001973:Bromodeoxyuridine
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