Objective The cerebral cortex consists of an extraordinary number and great diversity of neurons. Yet, how the cortical entity, with all its functional neuronal circuits, arises from the neural stem cells (NSCs) in the developing neuroepithelium is a major unsolved question in Neuroscience. Radial glia progenitors (RGPs) are responsible for producing nearly all neocortical neurons and a certain fraction of cortical glia including astrocytes. Our recent efforts provide evidence for a high degree of non-stochasticity and thus deterministic nature of RGP behavior in the mammalian neocortex. However, the cellular and molecular mechanisms controlling RGP lineage progression through proliferation, neurogenesis and especially gliogenesis are unknown. In a pursuit to obtain definitive insights into these fundamental questions we assess RGP lineage progression at the unprecedented single cell resolution, using the unique genetic MADM (Mosaic Analysis with Double Markers) technology. MADM offers an unparalleled approach to visualize and concomitantly manipulate sparse clones and small subsets of genetically defined neurons. Within the scope of this project we will use multidisciplinary experimental approaches to establish a research program with the following major objectives: We will 1) Functionally dissect the relative contribution of cell-autonomous intrinsic signaling and cell-non-autonomous effects in RGP lineage progression; 2) Define the principles of lineage progression in human RGPs in situ using MADM technology in cerebral organoid system; 3) Decipher the logic of glia lineage progression in the neocortex. The ultimate goal of the proposed research is to establish a definitive quantitative framework and mechanistic model of lineage progression in cortical NSCs. As such, the proposed research shall precipitate into extensive conceptual progress regarding the fundamental cellular and molecular principles of cerebral cortex development. Fields of science natural sciencesbiological sciencesneurobiologymedical and health sciencesclinical medicinepsychiatrymedical and health sciencesmedical biotechnologygenetic engineeringmedical and health sciencesmedical biotechnologycells technologiesstem cellsnatural sciencesmathematicspure mathematicsmathematical analysisfunctional analysis Keywords Cerebral Cortex Development Neural Stem Cells Lineage Single Cell Analysis Neurogenesis Gliogenesis Mosaic Analysis with Double Markers (MADM) Radial Glia Progenitors RGPs Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2016-COG - ERC Consolidator Grant Call for proposal ERC-2016-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA Net EU contribution € 1 996 030,00 Address Am Campus 1 3400 Klosterneuburg Austria See on map Region Ostösterreich Niederösterreich Wiener Umland/Nordteil Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 996 030,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA Austria Net EU contribution € 1 996 030,00 Address Am Campus 1 3400 Klosterneuburg See on map Region Ostösterreich Niederösterreich Wiener Umland/Nordteil Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 996 030,00