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.
Highlights
The small-GTPase Rac[1] is a key molecular regulator linking extracellular signals to actin cytoskeleton dynamics
We previously showed that in the early postnatal brain, ArhGAP15 is expressed in the olfactory bulbs, cortex and hippocampus[18]
The use of anti-βgal is justified by the fact that existing antibodies directed against ArhGAP15 detect unspecific signal, and cannot be reliably used. βgal/ArhGAP15 was detected nearly exclusively in Ctip2+ neurons in layer V, while it was not detected in Cux1+ and Tbr1+ neurons in other layers (Fig. 1C–G)
Summary
The small-GTPase Rac[1] is a key molecular regulator linking extracellular signals to actin cytoskeleton dynamics. 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. 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 Rac[1] regulators can result in conditions of ID, and that a tight regulation of Rac[1] activity is required to attain the full complexity of the cortical networks. Destabilization of the actin filament network, needed to transduce extracellular cues into vectorial flow of information[7,8]
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