The neocortex is the region of the brain responsible for cognitive function, sensory perception and consciousness, and as such, it is a recurrent subject of study in the neuroscientific field. In mammals, the neocortex is a highly organized, six-layered structure that contains hundreds of different neuronal cell types and a diverse range of glia. Our group is interested in the mechanisms invovled in the formation of this complex organ during development and the impact of these mechanisms on disease (1-3). One family of proteins that we are particularly interested in, are the ARHGAP family of signal transducers, as several of these genes are associated with multiple neurodevelopmental disorders including intellectual disability and Autism Spectrum Disorders (1, 2). ARHGAP proteins regulate the Rho family of cytoskeletal regulators through their GTPase-activating protein (GAP) catalytic activity as well as a variety of different other downstream pathways through a variety of different protein and lipid interaction domains (4). Our group is currently investigating, among others,  the role of the Major Depressive Disorder- associated gene, ARHGAP46/GMIP during the development of the neocortex (5). The aim of this project is to address the importance of the novel cellular and molecular roles of ARHGAP46 that we have identified, for both neuronal differentiation and the formation of the murine neocortex.

The project will involve: preparation and histological analysis of mouse brains including from a new ARHGAP46-deficient mouse line; ex-utero electroporation of constructs into the embryonic mouse brain; the preparation and manipulation of dissociated mouse cortical neuron cultures including transfection of DNA constructs; immunofluorescent staining and analysis of samples on confocal and fluorescent microscopes and biochemical assays for the activation of downstream pathways.

The working language of the Institute is English and the student will be expected to participate in weekly group and Institute-wide meetings. Research in the Institute is primarily focused on understanding the mechanims govering brain development. There are also weekly Neuroscience colloquia with high-profile guest speakers that the students are encouraged to attend.

References

1.            Schuster S, Rivalan M, Strauss U, Stoenica L, Trimbuch T, Rademacher N, et al. NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse. Mol Psychiatry. 2015;20(9):1120-31.

2.            Rosario M, Schuster S, Juttner R, Parthasarathy S, Tarabykin V, Birchmeier W. Neocortical dendritic complexity is controlled during development by NOMA-GAP-dependent inhibition of Cdc42 and activation of cofilin. Genes Dev. 2012;26(15):1743-57.

3.            Ambrozkiewicz MC, Schwark M, Kishimoto-Suga M, Borisova E, Hori K, Salazar-Lazaro A, et al. Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3 Ubiquitin Ligases and Intronic miR-140. Neuron. 2018;100(5):1097-115 e15.

4.            Amin E, Jaiswal M, Derewenda U, Reis K, Nouri K, Koessmeier KT, et al. Deciphering the Molecular and Functional Basis of RHOGAP Family Proteins: A SYSTEMATIC APPROACH TOWARD SELECTIVE INACTIVATION OF RHO FAMILY PROTEINS. J Biol Chem. 2016;291(39):20353-71.

5.            Tadokoro K, Hashimoto R, Tatsumi M, Kosuga A, Kamijima K, Kunugi H. The Gem interacting protein (GMIP) gene is associated with major depressive disorder. Neurogenetics. 2005;6(3):127-33.