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 language | English |
|---|---|
| Article number | 7254 |
| Journal | Scientific Reports |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Dec 1 2018 |
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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 journal › Article
}
TY - JOUR
T1 - Hyperactivity of Rac1-GTPase pathway impairs neuritogenesis of cortical neurons by altering actin dynamics
AU - Zamboni, Valentina
AU - Armentano, Maria
AU - Berto, Gaia
AU - Ciraolo, Elisa
AU - Ghigo, Alessandra
AU - Garzotto, Donatella
AU - Umbach, Alessandro
AU - Dicunto, Ferdinando
AU - Parmigiani, Elena
AU - Boido, Marina
AU - Vercelli, Alessandro
AU - El-Assawy, Nadia
AU - Mauro, Alessandro
AU - Priano, Lorenzo
AU - Ponzoni, Luisa
AU - Murru, Luca
AU - Passafaro, Maria
AU - Hirsch, Emilio
AU - Merlo, Giorgio R.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85046862830&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046862830&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-25354-3
DO - 10.1038/s41598-018-25354-3
M3 - Article
AN - SCOPUS:85046862830
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 7254
ER -