A role for Drosophila Drac1 in neurite outgrowth and synaptogenesis in the giant fiber system.
ABSTRACT Recent studies have shown the small GTPases, Rac1, Rho, and CDC42, to have a role in axon guidance. To assess their participation in synapse assembly and function we have expressed various forms of Drac1 in the giant fiber system of Drosophila. Overexpression of wild-type Drac1 in the giant fiber (GF) lead to a disruption in axonal morphology; axons often terminate prematurely in a large swelling in the target area but lack the normal lateral bend where the synapse with the jump motor neuron would normally be found. Electrophysiological assays revealed longer latencies and lowering following frequencies indicating defects in the synapse between the GF and the tergotrochanteral motor neuron (TTMn). Thickened abnormal GF dendrites were also observed in the brain. Overexpression of the dominant-negative form of Drac1, (N17), resulted in axons that produced extra branches in the second thoracic neuromere (T2); however, the synaptic connection to the TTMn was present and functioned normally. Conversely, expression of the constitutively active form, Drac1(V12), resulted in a complete lack of neurite outgrowth and this was also seen with overexpression of Dcdc42(V12). In the absence of a GF, these flies showed no response in the jump (TTM) or flight (DLM) muscles upon brain stimulation. Taken together these results show that the balance of actin polymerization and depolymerization determines local process outgrowth and thereby synapse structure and function.
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ABSTRACT: Brains undergo significant remodeling after traumatic brain injury (TBI). The Rho GTPase pathways control brain remodeling during development and under pathological conditions. However, how the Rho GTPase pathways are regulated in the brain after TBI remains largely unknown. This study utilized the rat fluid percussion injury model to investigate changes in the Rho GTPase pathways after TBI. The results showed that TBI leads to activation and translocation of RhoA and Rac1 proteins from cytosolic fraction to the membrane fraction after injury. Consistently, the Rho guanine nucleotide exchange factors GEF-H1 and Cool-2/αPix are significantly activated by dephosphorylation and accumulation in the cytosolic fractions during the post-TBI phase. Because the Rho GTPase pathways are key regulators of brain remodeling, these results depict regulatory mechanisms of the Rho GTPase pathways after TBI, and pave the way for the study of therapeutic agents targeting the Rho GTPase pathways for functional recovery after TBI.Journal of neurotrauma 04/2013; · 4.25 Impact Factor
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ABSTRACT: The formation of a neurite, the basis for axons and dendrites, begins with the concerted accumulation and organization of actin and microtubules. Whereas much is known about the proteins that play a role in these processes, because they perform similar functions in axon branching and filopodia formation, much remains to be discovered concerning the interaction of these individual cytoskeletal regulators during neurite formation. Here, we review the literature regarding various models of filopodial formation and the way in which proteins that control actin organization and polymerization induce neurite formation. Although several different regulators of actin polymerization are involved in neurite initiation, redundancy occurs between these regulators, as the effects of the loss of a single regulator can be mitigated by the addition of neurite-promoting substrates and proteins. Similar to actin dynamics, both microtubule stabilizing and destabilizing proteins play a role in neurite initiation. Furthermore, interactions between the actin and microtubule cytoskeleton are required for neurite formation. Several lines of evidence indicate that the interactions between these two components of the cytoskeleton are needed for force generation and for the localization of microtubules at sites of nascent neurites. The general theme that emerges is the existence of several central regulatory pathways on which extracellular cues converge to control and organize both actin and microtubules to induce the formation of neurites.Cell and Tissue Research 07/2014; · 3.33 Impact Factor
Article: Rac 'n Rho[Show abstract] [Hide abstract]
ABSTRACT: The small GTPases of the Rho subfamily constitute a group of evolutionarily conserved proteins that mediate signaling pathways that regulate a variety of cellular processes, many of which are associated with dynamic cytoskeletal reorganization. These processes determine the shape, adhesive properties, and movement of cells, and the Rho GTPases have therefore been implicated in the complex morphogenesis of tissues in developing multicellular organisms. The Drosophila genetic system has proved particularly useful in establishing the in vivo functions of several of the Rho GTPases and their associated signaling pathway components during development.Developmental Cell - DEV CELL. 01/2001; 1(3):321-331.