Projects: Systematic and targeted approaches to uncover molecular networks and mechanisms underlying human brain function and disease

Investigators: Annette Schenck (Group leader, mailto: a.schenck@antrg.umcn.nl), Jamie M. Kramer (Post-doc), Eiko K. de Jong (Post-doc), Christiane Zweier (postdoctoral guest scientist, collaboration with A. Rauch and A. Reis, University of Erlangen, Germany), Merel A.W. Oortveld (PhD student), Korinna Kochinke (PhD student), Eva van Engelen (Master’s student) and Daniela Kramer (Master’s student).

Summary:

We are a young, highly motivated and interdisciplinary research team that mainly focuses on dissecting molecular networks and mechanisms underlying human brain function and disease. Mutations in more than 400 genes are known to give rise to Mental Retardation (MR), providing an exciting starting point to study this problem. Accumulating evidence suggests that some MR genes operate together to control specific aspects of nervous system development and function. However, the function of most MR genes is unknown or poorly characterised at present. We aim at providing functional data for all MR genes and at systematically identifying their molecular connections. In order to be able to investigate the large number of genes, we use a powerful genetic model organism, the fruitfly Drosophila melanogaster. In flies, genes can be manipulated specifically in neurons with relative ease, and consequences for neuronal architecture, function and cognitive behaviour of the fly, such as learning and memory, can be studied and compared. Furthermore, we use the gained knowledge on MR gene function and the fruitfly as a model to search for genetic and chemical modifiers of fly „mental retardation“ phenotypes. This research identifies novel candidate genes and potential medication for humans. Recent data indicate that some forms of mental retardation indeed result from reversible inabilities of the nervous system, raising serious hope that impaired cognition can be treated. Beyond the expected fundamental insights into molecular pathways that wire the brain, our research program also aims at significantly contributing to such developments.
Advanced current projects in the lab focus on the 9q Subtelomeric Deletion Syndrome (9qSTDS), Arts and Pitt-Hopkins MR Syndromes and on Congenital Disorders of Glycosylation. Whereas these projects primarily aim to understand the neurological basis underlying their specific human disorders, they also serve as pilot projects for our systematic approaches to MR, as they continuously improve our knowledge on MR-relevant fly phenotypes.

Selected Publications:

Cliffe ST*, Kramer JM*, Hussain K*, Robben JH, de Jong EK, de Brouwer AP, Nibbeling E, Kamsteeg EJ, Wong M, Prendiville J, James C, Padidela R, Becknell C, van Bokhoven H, Deen PM, Hennekam RC, Lindeman R, Schenck A, Roscioli T, Buckley MF; *equal contribution. The SLC29A3 gene is mutated in pigmented hypertrichosis with Insulin dependent diabetes mellitus syndrome and interacts with the insulin signalling pathway. Hum Mol Genet, 2009, 18(12):2257-65.

Schenck, A., Goto-Silva, L., Collinet, C., Rhinn, M., Giner, A., Habermann, B., Brand, M., and Zerial, M. The endosomal protein APPL1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell, 2008, 133(3):486-497.

Qurashi, A., Sahin, B., Carrera, P., Gautreau, A., Schenck, A.* and Giangrande, A.*; *co-corresponding authors. HSPC300 and its role in Neuronal connectivity. Neural Develop, 2007, Sep 25,2:18.

Kim, Y, Sung, J.Y., Ceglia, I., Lee, K.W., Ahn, J., Halford, J.M., Kim, A., Kwak, S.P., Park, J.B., Ryu, S.H., Schenck, A., Bardoni, B., Scott, J.D., Nairn, A.C. and Greengard, P. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature, 2006, 442(7104):814-817.

Schenck, A., Qurashi A., Carrera, P., Bardoni B., Diebold, C., Schejter E.D., Mandel J.L. and Giangrande, A. WAVE/SCAR, a multifunctional complex coordinating different aspects of neuronal connectivity. Dev Biol, 2004, 274(2):260-270.

Schenck, A., Bardoni, B., Langmann, C., Harden, N., Mandel, J.L. and Giangrande, A. CYFIP/Sra-1 regulates neuronal connectivity in Drosophila and links the Rac1 small GTPase pathway to the Fragile X protein. Neuron, 2003, 38(6):887-98.

Funding:

• NCMLS tenure-track research fellowship (NCMLS)
• BMBF(German Federal Ministry of Education and Research) grant to the German Mental Retardation Network (MRnet)
• NWO (the Netherlands Organisation for Scientific Research): Innovational Research Incentives Scheme VIDI (NWO VIDI)
• NWO Aspasia award (NWO Aspasia)
• UMC St. Radboud Junior PI funds