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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number7254
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

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Pyramidal Cells
GTP Phosphohydrolases
Intellectual Disability
Actins
Actin Depolymerizing Factors
GTPase-Activating Proteins
Neurons
Growth Cones
Mutation
Monomeric GTP-Binding Proteins
Actin Cytoskeleton
Phosphorylation
Phenotype
Genes
In Vitro Techniques

ASJC Scopus subject areas

  • General

Cite this

Zamboni, V., Armentano, M., Berto, G., Ciraolo, E., Ghigo, A., Garzotto, D., ... Merlo, G. R. (2018). Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics. Scientific Reports, 8(1), [7254]. https://doi.org/10.1038/s41598-018-25354-3

Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics. / Zamboni, Valentina; Armentano, Maria; Berto, Gaia; Ciraolo, Elisa; Ghigo, Alessandra; Garzotto, Donatella; Umbach, Alessandro; Dicunto, Ferdinando; Parmigiani, Elena; Boido, Marina; Vercelli, Alessandro; El-Assawy, Nadia; Mauro, Alessandro; Priano, Lorenzo; Ponzoni, Luisa; Murru, Luca; Passafaro, Maria; Hirsch, Emilio; Merlo, Giorgio R.

In: Scientific Reports, Vol. 8, No. 1, 7254, 01.12.2018.

Research output: Contribution to journalArticle

Zamboni, V, Armentano, M, Berto, G, Ciraolo, E, Ghigo, A, Garzotto, D, Umbach, A, Dicunto, F, Parmigiani, E, Boido, M, Vercelli, A, El-Assawy, N, Mauro, A, Priano, L, Ponzoni, L, Murru, L, Passafaro, M, Hirsch, E & Merlo, GR 2018, 'Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics', Scientific Reports, vol. 8, no. 1, 7254. https://doi.org/10.1038/s41598-018-25354-3
Zamboni, Valentina ; Armentano, Maria ; Berto, Gaia ; Ciraolo, Elisa ; Ghigo, Alessandra ; Garzotto, Donatella ; Umbach, Alessandro ; Dicunto, Ferdinando ; Parmigiani, Elena ; Boido, Marina ; Vercelli, Alessandro ; El-Assawy, Nadia ; Mauro, Alessandro ; Priano, Lorenzo ; Ponzoni, Luisa ; Murru, Luca ; Passafaro, Maria ; Hirsch, Emilio ; Merlo, Giorgio R. / Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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