Rho kinase inhibition is essential during in vitro neurogenesis and promotes phenotypic rescue of human induced pluripotent stem cell-derived neurons with oligophrenin-1 loss of function

Research output: Contribution to journalArticle

Abstract

Rho-GTPases have relevant functions in various aspects of neuronal development, such as differentiation, migration, and synaptogenesis. Loss of function of the oligophrenin-1 gene (OPHN1) causes X-linked intellectual disability with cerebellar hypoplasia and leads to hyperactivation of the rho kinase (ROCK) pathway. ROCK mainly acts through phosphorylation of the myosin phosphatise targeting subunit 1, triggering actin-myosin contractility. We show that during in vitro neurogenesis, ROCK activity decreases from day 10 until terminal differentiation, whereas in OPHN1-deficient human induced pluripotent stem cells (h-iPSCs), the levels of ROCK are elevated throughout differentiation. ROCK inhibition favors neuronal-like appearance of h-iPSCs, in parallel with transcriptional up regulation of nuclear receptor NR4A1, which is known to induce neurite outgrowth. This study analyzed the morphological, biochemical, and functional features of OPHN1-deficient h-iPSCs and their rescue by treatment with the ROCK inhibitor fasudil, shedding light on the relevance of the ROCK pathway during neuronal differentiation and providing a neuronal model for human OPHN1 syndrome and its treatment.

Original languageEnglish
Pages (from-to)860-869
Number of pages10
JournalStem cells translational medicine
Volume5
Issue number7
DOIs
Publication statusPublished - 2016

Keywords

  • In vitro neurogenesis
  • Oligophrenin-1
  • Rho-kinase signaling
  • ROCK inhibitors (fasudil, Y-27632)

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology

Fingerprint Dive into the research topics of 'Rho kinase inhibition is essential during in vitro neurogenesis and promotes phenotypic rescue of human induced pluripotent stem cell-derived neurons with oligophrenin-1 loss of function'. Together they form a unique fingerprint.

  • Cite this