title: Human iPS Cell-Derived Neurons Uncover the Impact of Increased Ras Signaling in Costello Syndrome.
abstract: Increasing evidence implicates abnormal Ras signaling as a major contributor in neurodevelopmental disorders, yet how such signaling causes cortical pathogenesis is unknown. We examined the consequences of aberrant Ras signaling in the developing mouse brain and uncovered several critical phenotypes, including increased production of cortical neurons and morphological deficits. To determine whether these phenotypes are recapitulated in humans, we generated induced pluripotent stem (iPS) cell lines from patients with Costello syndrome (CS), a developmental disorder caused by abnormal Ras signaling and characterized by neurodevelopmental abnormalities, such as cognitive impairment and autism. Directed differentiation toward a neuroectodermal fate revealed an extended progenitor phase and subsequent increased production of cortical neurons. Morphological analysis of mature neurons revealed significantly altered neurite length and soma size in CS patients. This study demonstrates the synergy between mouse and human models and validates the use of iPS cells as a platform to study the underlying cellular pathologies resulting from signaling deficits.
  
  
  CONCLUSIONS
  Increasing evidence implicates Ras signaling dysfunction as a major contributor in psychiatric and neurodevelopmental disorders, such as cognitive impairment and autism, but the underlying cortical cellular pathogenesis remains unclear. This study is the first to reveal human neuronal pathogenesis resulting from abnormal Ras signaling and provides insights into how these phenotypic abnormalities likely contribute to neurodevelopmental disorders. We also demonstrate the synergy between mouse and human models, thereby validating the use of iPS cells as a platform to study underlying cellular pathologies resulting from signaling deficits. Recapitulating human cellular pathologies in vitro facilitates the future high throughput screening of potential therapeutic agents that may reverse phenotypic and behavioral deficits.
authors.affiliation: Departments of Ophthalmology.
authors.forename: Gemma E
authors.initials: GE
authors.lastname: Rooney
authors.affiliation: Orofacial Sciences.
authors.forename: Alice F
authors.initials: AF
authors.lastname: Goodwin
authors.affiliation: Anatomy.
authors.forename: Philippe
authors.identifier: http://orcid.org/0000-0002-5650-5521
authors.initials: P
authors.lastname: Depeille
authors.affiliation: Orofacial Sciences.
authors.forename: Amnon
authors.initials: A
authors.lastname: Sharir
authors.affiliation: Departments of Ophthalmology.
authors.forename: Claude M
authors.initials: CM
authors.lastname: Schofield
authors.affiliation: Psychiatry, and.
authors.forename: Erika
authors.identifier: http://orcid.org/0000-0002-2374-1528
authors.initials: E
authors.lastname: Yeh
authors.affiliation: Anatomy.
authors.forename: Jeroen P
authors.initials: JP
authors.lastname: Roose
authors.affiliation: Orofacial Sciences.
authors.forename: Ophir D
authors.initials: OD
authors.lastname: Klein
authors.affiliation: Pediatrics, University of California-San Francisco, San Francisco, California 94122.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rauen
authors.affiliation: Psychiatry, and.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Weiss
authors.affiliation: Departments of Ophthalmology, Erik.Ullian@ucsf.edu.
authors.forename: Erik M
authors.identifier: http://orcid.org/0000-0003-2077-8584
authors.initials: EM
authors.lastname: Ullian
mesh_terms: D000293:Adolescent; D000328:Adult; D002454:Cell Differentiation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D056685:Costello Syndrome / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D007223:Infant; D008297:Male; D008875:Middle Aged; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D018631:ras Proteins
keywords: Costello syndrome; Ras; cortical development; iPS cells; stem cells