Ph.D. Projects
Role of Rac GTPases and associated molecular complexes in neuronal development.
Rac proteins play fundamental roles in neuronal development. We have produced single and double knockout mice for the Rac1 and Rac3 GTPases expressed in peripheral neurons and in several regions of the central nervous system. While single knockout mice develop normally, double knockout mice show evident defects in the development of the brain and peripheral nervous system. In particular, the axonal pathways in the hippocampus are heavily affected, leading to epileptic seizures. Moreover the use of hippocampal neurons from these mice has shown strong impairment of synaptogenesis in double knockout neurons. The project available in the lab is aimed at understanding the function of Rac1 and Rac3 in neurons, by using hippocampal cultures from wildtype and knockout mice.
The functional analysis will include the study of a molecular network identified in our laboratory, which is functionally linked to the Rac GTPases, and is required for Rac-dependent neurite extension and synaptic development. This network includes the GIT1/PIX proteins regulating the activity of small GTPases, as well as PAK kinases and scaffolding proteins. The project will include the use of RNA interference to knockdown, and of mutants to overexpress components of the network, with the aim of clarifying the molecular events needed for setting up axon, dendrites and functional synapses. The GIT1 complexes localize at developing synapses in cultured hippocampal neurons.
Given the implication of PIX and PAK proteins in mental retardation, the understanding of these mechanisms will also help explaining molecular aspects relevant to mental disease.
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Di Cesare A, Paris S, et al. (2000). Nature Cell Biol. 2:521-530
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Totaro A, Paris S, Asperti C, de Curtis I. (2007). Mol Biol Cell. 18:5124-5138.
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de Curtis I. (2008). Dev Neurosci 30:47-58.
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Corbetta S, Gualdoni S, et al. (2009). FASEB J. 23:1347-1357.
