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.