INIMEC - CONICET   05467
INSTITUTO DE INVESTIGACION MEDICA MERCEDES Y MARTIN FERREYRA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
IQGAP1: role in spines morphogenesis
Autor/es:
IGNACIO JAUSORO, MONICA SÁNCHES, FLORENCIA HEREDIA, ALFREDO CÁCERES
Lugar:
Heraklion
Reunión:
Workshop; • Cell Biology of The Neuron: Polarity, Plasticity and Regeneration.; 2011
Institución organizadora:
EMBO
Resumen:
In this paper we show that IQGAP1 is localizedin dendritic spinesof neurons between 18 and 21 DIV. This finding is interesting because this proteinhas different functions as a regulator of the cytoskeleton. In particular, IQGAP1 hasbeen postulated asa key regulatorof the dynamicsand organization of the actin cytoskeleton in non-neural cells, however, this proteinfunctions in the nervous system have not been investigated in detail. Large number of experiments indicate that actin dynamics regulatesmorphology and motilityof dendritic spines in neuronal cultures (Zito et al., 2004). A varietyof ABPs (actin binding proteins) regulate the assembly, disassembly and stability of actin filaments. Some of these proteins have also shown a strong impact on thedynamics of actinin dendritic spines. Among those that havebeen identified are complex Arp2 / 3, cortactin, ADF /cofilin, profilin, gelsolin, debrina, neurabina(reviewed in (Ethell and Pasquale, 2005) and IQGAP1 (Schrick et al., 2007). In relation to the above about the ABPs is well known that IQGAPs are essential for the accumulation of actin at specific sites that need a high turnover of actin, like cytokinesis ring. In addition, there are data showing that IQGAP1 is recruited sequentially before actin filaments begins to be visible (Lippincott and Li, 1998). These and other results suggest that IQGAPs proteins are important in the spatiotemporal regulation of actin assembly. In accordance with the above, our results showed how the silencing of IQGAP1 in adult neuronal cultures reduces the number of dendritic spines per micron, which indicates that this protein is essential in the formation of dendritic spines, and may be exerting some of the functions referred to above. Our observations show that overexpressionof IQGAP1 promotesspinogenesis phenomenon, and that different domainsof IQGAP1 regulatedifferent morphological features ofdendritic spines. Our observationsshow that overexpressionof IQGAP1 promotesspinogenesis phenomenon, and that different domainsof IQGAP1 regulatedifferent morphological features ofdendritic spines. Our results indicate thatthe mere overexpression of the wild proteinin adult neurons producesan increase in the number, length andarea of the headof the spines. On other hand, we have demonstrated that domain that  interacts directly with F-actin (CHD)  is essential for the formation of the head of the spine.                 Moreover, we suggest that the function of this domain in the head of the spine is associated particularly with the formation of particular array of actin, like actin meshwork. Taken together, these data indicate that IQGAP1 regulatesthe dynamics and the formation of the actin meshwork in the headof the spines, whichplays an important role in the maintenance and formation of the PSD, playing afundamental role in synaptic transmission. In addition, our results clearly show that deletion of the GRD domain (Cdc42-GTP interacting domain) of IQGAP1 reduces thenumber of spines withneck and increases the number of stubby spines. Also, thebest characterized members of the Rho family of GTPases (RhoA, Rac1and Cdc42) have a strong influence on the morphogenesis of dendritic spines by regulating actin dynamics in these structures (Newey et al., 2005). All mentioned above, also our results indicate that interactionIQGAP1/Cdc42 is essentialin regulating actin dynamics on dendritic spinesneck. Moreover, we can say that the formation of the neck of a dendritic spine requires the activity of Cdc42and IQGAP1 to promoteformation and/or elongationof actin bundlesthat compose it. Finally, our results showed that deletionof carboxyl-terminal domain of IQGAP1 does not affect the density of dendritic spines, probably this deletion was not enough and does not affect the interactionwith TIPs, we need to do some experimets to test this. All together theseresults show anovel function ofIQGAP1 in hippocampalneurons, as well as an interesting and new regulatory mechanism in morphogenesisof dendritic spines, which suggests independent regulation of the actin dynamics in neck and head of the spine. Consistent with theabove, we showthat deletion of theCHD domain, GRD, and CT of IQGAP1 does not alterthe localization of PSD-95-GFP. In this work we show that regulation of the actin network in the spine headis mediated by direct interaction of IQGAP1 withF-actin. Moreover, we postulate that the CHD domain is essential for theformation of thisnetwork and its rolein the head ofthe spine ismediated by the complexArp2/3, and we reported that the decreased expression of complex Arp2/3 delete spinogenesis effect generated by over-expression ofwild-type IQGAP1, suggesting the involvement of this complexdownstream of IQGAP1. Another interesting aspect of IQGAP1 is its ability to modulate microtubule dynamics, and the effect that this could produce in actin dynamics. These features suggest to IQGAP1 as a key regulator of communication between the microtubule cytoskeletonand actin, whichmay involve the recruitment of other space-time modulators of actin dynamics. Recent studies showed that neural activity effectivelyincreased both the number of spines that were invadedby MT dynamic, as the duration of the invasion. In this regard our results are novel and essentialbackground for understandingphenomena involving spinogenesis and synaptic activity. That is why it is essential to elucidate how all these molecular mechanisms converge on the actin cytoskeleton and ABPs, in addition to determine their involvement in complex brain functions.