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In vivo analysis of DISC1 function in synaptogenesis and axonal transport (DISC1 & Axogenesis)
Start date: Apr 1, 2011, End date: Mar 31, 2015 PROJECT  FINISHED 

Schizophrenia is a highly hereditable psychological disease that affects up to 1% of the world population. This pathology causes devastating neurological symptoms. A great advance in understanding the basic biological processes affected in schizophrenia came from the discovery of some of the genes that when mutated represent a risk factor for the development of the disease, most likely acting in combination among each other and with environmental factors. One of the best established of these susceptibility genes is a called Disrupted-in-schizophrenia-1 (DISC1). DISC1 has been implicated in many fundamental process and it likely to perform many tasks during the normal development and function of neurons. I am proposing to investigate the involvement of DISC1 in the transport of cargoes along the neuronal axon. This phenomenon is of crucial importance for normal brain function since it allows the trafficking of proteins and organelles between the cell body of the neurons and the synapses at the periphery, and vice versa. There are indications that DISC1 may be regulating this bidirectional transport by interacting with microtubule associated motors and that this process may be altered in schizophrenic patients. Using zebrafish I will be able to observe this phenomenon in vivo, with a detail resolution that is not possible in humans or other mammals. Using a combination of experimental tools including, zebrafish mutants for the DISC1 locus, dominant negative approaches and shRNA knock down, I will assay the function of DISC1 in single neurons separating its later role in neuronal function from early ones. The brain of zebrafish larvae is in fact transparent and small enough to allow the direct observations of fluorescent proteins in single axons. Furthermore, these dynamic processes are highly conserved between fish and humans and what we learn from the fish model will tell us more about DISC1 function in humans as well.
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