Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics

Abstract The small-GTPase Rac1 is a key molecular regulator linking extracellular signals to actin cytoskeleton dynamics. Loss-of-function mutations in RAC1 and other genes of the Rac signaling pathway have been implicated in the pathogenesis of Intellectual Disability (ID). The Rac1 activity is neg...

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Autores principales:	Valentina Zamboni, Maria Armentano, Gaia Berto, Elisa Ciraolo, Alessandra Ghigo, Donatella Garzotto, Alessandro Umbach, Ferdinando DiCunto, Elena Parmigiani, Marina Boido, Alessandro Vercelli, Nadia El-Assawy, Alessandro Mauro, Lorenzo Priano, Luisa Ponzoni, Luca Murru, Maria Passafaro, Emilio Hirsch, Giorgio R. Merlo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/638ec94828f043b0b3fe8bf5f8131542
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spelling	oai:doaj.org-article:638ec94828f043b0b3fe8bf5f81315422021-12-02T12:33:00ZHyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics10.1038/s41598-018-25354-32045-2322https://doaj.org/article/638ec94828f043b0b3fe8bf5f81315422018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25354-3https://doaj.org/toc/2045-2322Abstract The small-GTPase Rac1 is a key molecular regulator linking extracellular signals to actin cytoskeleton dynamics. Loss-of-function mutations in RAC1 and other genes of the Rac signaling pathway have been implicated in the pathogenesis of Intellectual Disability (ID). The Rac1 activity is negatively controlled by GAP proteins, however the effect of Rac1 hyperactivity on neuronal networking in vivo has been poorly studied. ArhGAP15 is a Rac-specific negative regulator, expressed in the main subtypes of pyramidal cortical neurons. In the absence of ArhGAP15, cortical pyramidal neurons show defective neuritogenesis, delayed axonal elongation, reduced dendritic branching, both in vitro and in vivo. These phenotypes are associated with altered actin dynamics at the growth cone due to increased activity of the PAK-LIMK pathway and hyperphosphorylation of ADF/cofilin. These results can be explained by shootin1 hypo-phosphorylation and uncoupling with the adhesion system. Functionally, ArhGAP15 −/− mice exhibit decreased synaptic density, altered electroencephalographic rhythms and cognitive deficits. These data suggest that both hypo- and hyperactivation of the Rac pathway due to mutations in Rac1 regulators can result in conditions of ID, and that a tight regulation of Rac1 activity is required to attain the full complexity of the cortical networks.Valentina ZamboniMaria ArmentanoGaia BertoElisa CiraoloAlessandra GhigoDonatella GarzottoAlessandro UmbachFerdinando DiCuntoElena ParmigianiMarina BoidoAlessandro VercelliNadia El-AssawyAlessandro MauroLorenzo PrianoLuisa PonzoniLuca MurruMaria PassafaroEmilio HirschGiorgio R. MerloNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-16 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Valentina Zamboni Maria Armentano Gaia Berto Elisa Ciraolo Alessandra Ghigo Donatella Garzotto Alessandro Umbach Ferdinando DiCunto Elena Parmigiani Marina Boido Alessandro Vercelli Nadia El-Assawy Alessandro Mauro Lorenzo Priano Luisa Ponzoni Luca Murru Maria Passafaro Emilio Hirsch Giorgio R. Merlo Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics
description	Abstract The small-GTPase Rac1 is a key molecular regulator linking extracellular signals to actin cytoskeleton dynamics. Loss-of-function mutations in RAC1 and other genes of the Rac signaling pathway have been implicated in the pathogenesis of Intellectual Disability (ID). The Rac1 activity is negatively controlled by GAP proteins, however the effect of Rac1 hyperactivity on neuronal networking in vivo has been poorly studied. ArhGAP15 is a Rac-specific negative regulator, expressed in the main subtypes of pyramidal cortical neurons. In the absence of ArhGAP15, cortical pyramidal neurons show defective neuritogenesis, delayed axonal elongation, reduced dendritic branching, both in vitro and in vivo. These phenotypes are associated with altered actin dynamics at the growth cone due to increased activity of the PAK-LIMK pathway and hyperphosphorylation of ADF/cofilin. These results can be explained by shootin1 hypo-phosphorylation and uncoupling with the adhesion system. Functionally, ArhGAP15 −/− mice exhibit decreased synaptic density, altered electroencephalographic rhythms and cognitive deficits. These data suggest that both hypo- and hyperactivation of the Rac pathway due to mutations in Rac1 regulators can result in conditions of ID, and that a tight regulation of Rac1 activity is required to attain the full complexity of the cortical networks.
format	article
author	Valentina Zamboni Maria Armentano Gaia Berto Elisa Ciraolo Alessandra Ghigo Donatella Garzotto Alessandro Umbach Ferdinando DiCunto Elena Parmigiani Marina Boido Alessandro Vercelli Nadia El-Assawy Alessandro Mauro Lorenzo Priano Luisa Ponzoni Luca Murru Maria Passafaro Emilio Hirsch Giorgio R. Merlo
author_facet	Valentina Zamboni Maria Armentano Gaia Berto Elisa Ciraolo Alessandra Ghigo Donatella Garzotto Alessandro Umbach Ferdinando DiCunto Elena Parmigiani Marina Boido Alessandro Vercelli Nadia El-Assawy Alessandro Mauro Lorenzo Priano Luisa Ponzoni Luca Murru Maria Passafaro Emilio Hirsch Giorgio R. Merlo
author_sort	Valentina Zamboni
title	Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics
title_short	Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics
title_full	Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics
title_fullStr	Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics
title_full_unstemmed	Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics
title_sort	hyperactivity of rac1-gtpase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/638ec94828f043b0b3fe8bf5f8131542
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Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics

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