In vitro characterization of neurite extension using induced pluripotent stem cells derived from lissencephaly patients with TUBA1A missense mutations

Yohei Bamba, Tomoko Shofuda, Mitsuhiro Kato, Ritsuko K. Pooh, Yoko Tateishi, Jun Ichi Takanashi, Hidetsuna Utsunomiya, Miho Sumida, Daisuke Kanematsu, Hiroshi Suemizu, Yuichiro Higuchi, Wado Akamatsu, Denis Gallagher, Freda D. Miller, Mami Yamasaki, Yonehiro Kanemura, Hideyuki Okano

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Background: Lissencephaly, or smooth brain, is a severe congenital brain malformation that is thought to be associated with impaired neuronal migration during corticogenesis. However, the exact etiology of lissencephaly in humans remains unknown. Research on congenital diseases is limited by the shortage of clinically derived resources, especially for rare pediatric diseases. The research on lissencephaly is further limited because gyration in humans is more evolved than that in model animals such as mice. To overcome these limitations, we generated induced pluripotent stem cells (iPSCs) from the umbilical cord and peripheral blood of two lissencephaly patients with different clinical severities carrying alpha tubulin (TUBA1A) missense mutations (Patient A, p.N329S; Patient B, p.R264C). Results: Neural progenitor cells were generated from these iPSCs (iPSC-NPCs) using SMAD signaling inhibitors. These iPSC-NPCs expressed TUBA1A at much higher levels than undifferentiated iPSCs and, like fetal NPCs, readily differentiated into neurons. Using these lissencephaly iPSC-NPCs, we showed that the neurons derived from the iPSCs obtained from Patient A but not those obtained from Patient B showed abnormal neurite extension, which correlated with the pathological severity in the brains of the patients. Conclusion: We established iPSCs derived from lissencephaly patients and successfully modeled one aspect of the pathogenesis of lissencephaly in vitro using iPSC-NPCs and iPSC-derived neurons. The iPSCs from patients with brain malformation diseases helped us understand the mechanism underlying rare diseases and human corticogenesis without the use of postmortem brains.

Original languageEnglish
Article number70
JournalMolecular brain
Volume9
Issue number1
DOIs
Publication statusPublished - 2016 Jul 19

Keywords

  • Induced pluripotent stem cells
  • Lissencephaly
  • Neural progenitor cells
  • TUBA1A

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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