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.

Compagnucci, C., Barresi, S., Petrini, S., Billuart, P., Piccini, G., Chiurazzi, P., Alfieri, P., Bertini, E., Zanni, G., 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, <<STEM CELLS TRANSLATIONAL MEDICINE>>, 2016; 5 (7): 860-869. [doi:10.5966/sctm.2015-0303] [http://hdl.handle.net/10807/95381]

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

Chiurazzi, Pietro;
2016

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.
2016
Inglese
Compagnucci, C., Barresi, S., Petrini, S., Billuart, P., Piccini, G., Chiurazzi, P., Alfieri, P., Bertini, E., Zanni, G., 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, <<STEM CELLS TRANSLATIONAL MEDICINE>>, 2016; 5 (7): 860-869. [doi:10.5966/sctm.2015-0303] [http://hdl.handle.net/10807/95381]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/95381
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