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

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6 Citations (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.

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

Fingerprint

Induced Pluripotent Stem Cells
rho-Associated Kinases
Neurogenesis
Myosins
Neurons
Nuclear Receptor Subfamily 4, Group A, Member 1
Genes
X-Linked Genes
rho GTP-Binding Proteins
Intellectual Disability
Actins
Up-Regulation
Phosphorylation
Therapeutics
In Vitro Techniques
Inhibition (Psychology)

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology

Cite this

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title = "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",
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.",
keywords = "In vitro neurogenesis, Oligophrenin-1, Rho-kinase signaling, ROCK inhibitors (fasudil, Y-27632)",
author = "Claudia Compagnucci and Sabina Barresi and Stefania Petrini and Pierre Billuart and Giorgia Piccini and Pietro Chiurazzi and Paolo Alfieri and Enrico Bertini and Ginevra Zanni",
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T1 - 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

AU - Compagnucci, Claudia

AU - Barresi, Sabina

AU - Petrini, Stefania

AU - Billuart, Pierre

AU - Piccini, Giorgia

AU - Chiurazzi, Pietro

AU - Alfieri, Paolo

AU - Bertini, Enrico

AU - Zanni, Ginevra

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - In vitro neurogenesis

KW - Oligophrenin-1

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KW - ROCK inhibitors (fasudil, Y-27632)

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