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

Claudia Compagnucci, Sabina Barresi, Stefania Petrini, Pierre Billuart, Giorgia Piccini, Pietro Chiurazzi, Paolo Alfieri, Enrico Bertini, Ginevra Zanni

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

12 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)860-869
Numero di pagine10
RivistaStem cells translational medicine
Volume5
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Cell Biology
  • Cell Differentiation
  • Cell Shape
  • Cells, Cultured
  • Cytoskeletal Proteins
  • Developmental Biology
  • GTPase-Activating Proteins
  • Humans
  • In vitro neurogenesis
  • Induced Pluripotent Stem Cells
  • Models, Biological
  • Mutation
  • Nervous System Diseases
  • Neurogenesis
  • Neurons
  • Nuclear Proteins
  • Oligophrenin-1
  • Phenotype
  • ROCK inhibitors (fasudil, Y-27632)
  • Rho-kinase signaling
  • Syndrome
  • rho-Associated Kinases

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