Human iPS Cell-Derived Neurons Uncover the Impact of Increased Ras Signaling in Costello Syndrome
Year: 2016
Type: article
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. SIGNIFICANCE STATEMENT: 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.
Source: Journal of Neuroscience
Institution: University of California, San Francisco
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: Research to Prevent Blindness, Simons Foundation Autism Research Initiative, National Institutes of Health, National Institute of Mental Health, National Eye Institute, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1613908829, G285083758, G2916827764, G3162967742, G3609659413, G4108569856, G499696825, G5204774311, G5692985264, G616159751, Dissecting Epistasis and Pleiotropy in Autism towards Personalized Medicine, THE ROLE OF ASTROCYTES IN PLASTICITY AND DISEASE., G7952167829, G9000011897, G9000327094, Defining the Unique Properties of the Distinct Signaling Machinery Used by the TCR
OpenAlex ID: W2224366145