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RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex.
Catlett, Timothy S; Onesto, Massimo M; McCann, Alec J; Rempel, Sarah K; Glass, Jennifer; Franz, David N; Gómez, Timothy M.
Afiliación
  • Catlett TS; Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • Onesto MM; Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • McCann AJ; Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • Rempel SK; Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • Glass J; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Franz DN; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • Gómez TM; Department of Neuroscience, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. tmgomez@wisc.edu.
Nat Commun ; 12(1): 2589, 2021 05 10.
Article en En | MEDLINE | ID: mdl-33972524
Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections formed during development which may contribute to symptoms of TSC, such as intellectual disabilities, autism, and epilepsy. Yet models examining the molecular basis for axonal guidance defects in developing human neurons have not been developed. Here, we generate human induced pluripotent stem cell (hiPSC) lines from a patient with TSC and genetically engineer counterparts and isogenic controls. By differentiating hiPSCs, we show that control neurons respond to canonical guidance cues as predicted. Conversely, neurons with heterozygous loss of TSC2 exhibit reduced responses to several repulsive cues and defective axon guidance. While TSC2 is a known key negative regulator of MTOR-dependent protein synthesis, we find that TSC2 signaled through MTOR-independent RHOA in growth cones. Our results suggest that neural network connectivity defects in patients with TSC may result from defects in RHOA-mediated regulation of cytoskeletal dynamics during neuronal development.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Esclerosis Tuberosa / Proteína de Unión al GTP rhoA / Neurogénesis / Células Madre Pluripotentes Inducidas / Orientación del Axón / Proteína 2 del Complejo de la Esclerosis Tuberosa / Red Nerviosa / Neuronas Tipo de estudio: Guideline / Prognostic_studies Límite: Adolescent / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Esclerosis Tuberosa / Proteína de Unión al GTP rhoA / Neurogénesis / Células Madre Pluripotentes Inducidas / Orientación del Axón / Proteína 2 del Complejo de la Esclerosis Tuberosa / Red Nerviosa / Neuronas Tipo de estudio: Guideline / Prognostic_studies Límite: Adolescent / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos