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Department of Functional Genomics

The department studies the presynaptic nerve terminal in health and disease. It also contributes to the understanding of complex traits in rodents and humans.

The department studies the presynaptic nerve terminal in health and disease and also contributes to the understanding of complex traits in rodents and humans.
In our studies of the nerve terminal, we aim to understand the gene networks that orchestrate the secretion of diverse chemical signals such as classical neurotransmitters from synaptic vesicles and large dense core vesicles. In our complex trait studies we aim to systematically dissect complex behavior, especially cognition, in terms of the underlying network of latent traits, gene networks, genetic variation and environmental factors and to understand disease mechanisms.

For our secretion studies, we use model organisms. Mostly mutant mice and in vitro preparations, such as primary neurons and secretory cells in culture. These models are studied, using a variety of functional assays. They range from electronmicroscopy, molecular biology, protein chemistry and immunocytochemistry to life cell imaging, electrophysiology and behavioral phenotyping. We use both human and mouse populations for our complex trait studies: clinical cohorts, twins and samples from the general population and common inbred mouse lines, recombinant inbred lines, transposon mice and knock-out/knock-in mice. We study these populations, using genome wide association studies, gene network analyses and phenotypic modelling. We also apply high-throughput, automated behavioral assessments in rodents.

FGA is one of the founding partners of the Dutch NeuroBsik Mouse Phenomics consortium and three European consortia: EU-synapse, Eurospin and SynSys.

FGA consist of 40-50 scientists and technicians. Most of these scientists are part of one of the 6 research teams (see green box left).
10 recent papers of the department (members of FGA are underlined):

1) Nair R, Lauks J, Jung S, Cooke NE, de Wit H, Brose N, Kilimann MW, Verhage M, Rhee J. Neurobeachin regulates neurotransmitter receptor trafficking to synapses.J Cell Biol. 2013;200(1):61-80.

2) van de Bospoort R, Farina M, Schmitz SK, de Jong A, de Wit H, Verhage M, Toonen RF. Munc13 controls the location and efficiency of dense-core vesicle release in neurons. J Cell Biol. 2012199(6):883-91.

3) de Jong AP, Schmitz SK, Toonen RF, Verhage M. Dendritic position is a major determinant of presynaptic strength. J Cell Biol. 2012; 197(2):327-37.

4) Lips ES, Cornelisse LN, Toonen RF, Min JL, Hultman CM; the International Schizophrenia Consortium, Holmans PA, O’Donovan MC, Purcell SM, Smit AB, Verhage M, Sullivan PF, Visscher PM, Posthuma D. Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia. Mol Psychiatry. 2012;17(10): 996-1006.

5) Mohrmann R, de Wit H, Verhage M, Neher E, Sørensen JB. (2010) Fast vesicle fusion in living cells requires at least three SNARE complexes.
Science 330(6003):502-5.

6) Groffen AJ, Martens S, Díez Arazola R, Cornelisse LN, Lozovaya N, de Jong AP, Goriounova NA, Habets RL, Takai Y, Borst JG, Brose N, McMahon HT, Verhage M. (2010) Doc2b is a high-affinity Ca2+ sensor for spontaneous neurotransmitter release. Science 327:1614-8.

7) Verhage M. (2009) Organelle docking: R-SNAREs are late. Proc Natl Acad Sci U S A. 106:19745-6.

8) de Wit H, Walter AM, Milosevic I, Gulyás-Kovács A, Riedel D, Sørensen JB, Verhage M (2009) Synaptotagmin-1 docks secretory vesicles to syntaxin-1/SNAP-25 acceptor complexes. Cell 138:935-46

9) Gerber SH, Rah JC, Min SW, Liu X, de Wit H, Dulubova I, Meyer AC, Rizo J, Arancillo M, Hammer RE, Verhage M, Rosenmund C, Südhof TC (2008) Conformational switch of syntaxin-1 controls synaptic vesicle fusion. Science 321:1507-10.

10) Wierda KD, Toonen RF, de Wit H, Brussaard AB, Verhage M (2007) Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity. Neuron 54:275-90.

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