Abstract
Rho-class small GTPases are implicated in basic cellular processes at nearly all brain developmental steps, from neurogenesis and migration to axon guidance and synaptic plasticity. GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Rho GTPases are highly regulated by a complex set of activating (GEFs) and inactivating (GAPs) partners, via protein:protein interactions (PPI). Misregulated RhoA, Rac1/Rac3 and cdc42 activity has been linked with intellectual disability (ID) and other neurodevelopmental conditions that comprise ID. All genetic evidences indicate that in these disorders the RhoA pathway is hyperactive while the Rac1 and cdc42 pathways are consistently hypoactive. Adopting cultured neurons for in vitro testing and specific animal models of ID for in vivo examination, the endophenotypes associated with these conditions are emerging and include altered neuronal networking, unbalanced excitation/inhibition and altered synaptic activity and plasticity. As we approach a clearer definition of these phenotype(s) and the role of hyper- and hypo-active GTPases in the construction of neuronal networks, there is an increasing possibility that selective inhibitors and activators might be designed via PPI, or identified by screening, that counteract the misregulation of small GTPases and result in alleviation of the cognitive condition. Here we review all knowledge in support of this possibility.
Highlights
Small GTPases of the Rho class comprise a set of highly conserved signaling GTPases, including RhoA, RhoB and RhoC, Rac1, Rac2, Rac3 and RhoG and cdc42, TC10/RhoQ and TCL/RhoJ
The GTP/GDP cycle is regulated by complex protein:protein interactions (PPI) between the GTPase and various partners that either increase (Guanine nucleotide Exchange Factors, GEFs) or decrease (GTPase-activating proteins, GAP) their function to activate downstream targets
The first mutation described is a breakpoint between exons 6 and 7 of ARHGEF9 resulting in the absence of full-length transcripts in patients with Intellectual Disability (ID) [140]
Summary
Small GTPases of the Rho class comprise a set of highly conserved signaling GTPases, including RhoA, RhoB and RhoC (the Rho subclass), Rac, Rac, Rac and RhoG (the Rac subclass) and cdc, TC10/RhoQ and TCL/RhoJ (the cdc subclass). Rac and cdc regulate neuronal migration and the formation of leading process of migrating neurons via the activation of the downstream c-Jun N-terminal kinase (JNK)-microtubule pathway through the association with IQ motif containing GTPase activating protein 1 (IQGAP1) [27,28]. The control of cytoskeletal dynamics is essential for axonogenesis, dendritogenesis, axon guidance and neuronal migration [3,4], required for the construction of the excitatory and inhibitory networks and their complexity For this reason, changes of the spatiotemporal activity of small GTPases, such as those due to mutations in GAPs and GEFs, affect neuronal migration, dendrite extension and complexity, axon extension and guidance, and spine shape and plasticity, resulting in ID and other cognitive deficits. Whether this could represent a unifying mechanisms that participates in the endophenotype leading to ID remains to be further investigated
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have