期刊
JOURNAL OF NEUROSCIENCE
卷 36, 期 1, 页码 142-152出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1547-15.2016
关键词
cortical development; Costello syndrome; iPS cells; Ras; stem cells
资金
- Allen Distinguished Investigator Award
- National Institutes of Health New Innovator Award [1DP2OD006507-01]
- National Institutes of Health [MH 5R01MH099595, NEI EY002162]
- Research to Prevent Blindness Unrestricted Grant
- Core Grant for Vision Research
- National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [5R01AR062165, DP2 0D007449]
- SFARI Award [345471]
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.
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