Human iPS cell-derived neurons uncover the impact of increased ras signaling in costello syndrome

Gemma E. Rooney, Alice F. Goodwin, Philippe Depeille, Amnon Sharir, Claude M. Schofield, Erika Yeh, Jeroen P. Roose, Ophir D. Klein, Katherine A. Rauen, Lauren A. Weiss, Erik M. Ullian

Research output: Contribution to journalArticlepeer-review


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 andhumanmodels and validates the use of iPS cells as a platform to study the underlying cellular pathologies resulting from signaling deficits.

Original languageAmerican English
Pages (from-to)142-152
Number of pages11
JournalJournal of Neuroscience
Issue number1
StatePublished - 6 Jan 2016
Externally publishedYes


  • Cortical development
  • Costello syndrome
  • IPS cells
  • Ras
  • Stem cells

All Science Journal Classification (ASJC) codes

  • General Neuroscience


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