title: Tuberous sclerosis complex proteins control axon formation.
abstract: Axon formation is fundamental for brain development and function. TSC1 and TSC2 are two genes, mutations in which cause tuberous sclerosis complex (TSC), a disease characterized by tumor predisposition and neurological abnormalities including epilepsy, mental retardation, and autism. Here we show that Tsc1 and Tsc2 have critical functions in mammalian axon formation and growth. Overexpression of Tsc1/Tsc2 suppresses axon formation, whereas a lack of Tsc1 or Tsc2 function induces ectopic axons in vitro and in the mouse brain. Tsc2 is phosphorylated and inhibited in the axon but not dendrites. Inactivation of Tsc1/Tsc2 promotes axonal growth, at least in part, via up-regulation of neuronal polarity SAD kinase, which is also elevated in cortical tubers of a TSC patient. Our results reveal key roles of TSC1/TSC2 in neuronal polarity, suggest a common pathway regulating polarization/growth in neurons and cell size in other tissues, and have implications for the understanding of the pathogenesis of TSC and associated neurological disorders and for axonal regeneration.
authors.affiliation: The F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Choi
authors.forename: Alessia
authors.initials: A
authors.lastname: Di Nardo
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kramvis
authors.forename: Lynsey
authors.initials: L
authors.lastname: Meikle
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.forename: Mustafa
authors.initials: M
authors.lastname: Sahin
authors.forename: Xi
authors.initials: X
authors.lastname: He
mesh_terms: D000818:Animals; D001369:Axons; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D018274:Electroporation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C523084:BRSK1 protein, human; D017346:Protein Serine-Threonine Kinases
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