title: Impaired Reelin-Dab1 Signaling Contributes to Neuronal Migration Deficits of Tuberous Sclerosis Complex.
abstract: Tuberous sclerosis complex (TSC) is associated with neurodevelopmental abnormalities, including defects in neuronal migration. However, the alterations in cell signaling mechanisms critical for migration and final positioning of neurons in TSC remain unclear. Our detailed cellular analyses reveal that reduced Tsc2 in newborn neurons causes abnormalities in leading processes of migrating neurons, accompanied by significantly delayed migration. Importantly, we demonstrate that Reelin-Dab1 signaling is aberrantly regulated in TSC mouse models and in cortical tubers from TSC patients owing to enhanced expression of the E3 ubiquitin ligase Cul5, a known mediator of pDab1 ubiquitination. Likewise, mTORC1 activation by Rheb overexpression generates similar neuronal and Reelin-Dab1 signaling defects, and directly upregulates Cul5 expression. Inhibition of mTORC1 by rapamycin treatment or by reducing Cul5 largely restores normal leading processes and positioning of migrating neurons. Thus, disrupted Reelin-Dab1 signaling is critically involved in the neuronal migration defects of TSC.
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Uk Yeol
authors.initials: UY
authors.lastname: Moon
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Park
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Raehee
authors.initials: R
authors.lastname: Park
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Cho
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Graduate Program of Biomedical Sciences, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Lucinda J
authors.initials: LJ
authors.lastname: Hughes
authors.affiliation: Department of Human Genetics, Emory University, School of Medicine, Atlanta, GA 30322, USA.
authors.forename: James
authors.initials: J
authors.lastname: McKenna
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Obstetrics Gynecology and Reproductive Sciences, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Goetzl
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Seo-Hee
authors.initials: SH
authors.lastname: Cho
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Neurology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Crino
authors.affiliation: Department of Human Genetics, Emory University, School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gambello
authors.affiliation: Shriners Hospitals Pediatric Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA. Electronic address: seonhee.kim@temple.edu.
authors.forename: Seonhee
authors.initials: S
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D000091042:Reelin Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C496871:CUL5 protein, human; D015816:Cell Adhesion Molecules, Neuronal; D044842:Cullin Proteins; C115785:DAB1 protein, human; C103773:Dab1 protein, mouse; D016326:Extracellular Matrix Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C531145:cullin5 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D020123:Sirolimus