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Molecular Mechanisms of Cerebral Cortex Development

Final Report Summary - MOMECODE (Molecular Mechanisms of Cerebral Cortex Development)

The mammalian cerebral cortex is responsible for higher cognitive functions such as perception, consciousness, acquiring and processing information. The neocortex represents the part of the cerebral cortex which has evolved the most and is organized into six distinct laminae, each composed of a rich diversity of cell types. Radial glia progenitors (RGPs) are responsible for producing all neocortical neurons and certain glia lineages. The mechanisms of cortical neuron production and glia genesis, and how cortical neurons and glia coalesce into defined laminae and form specific connections with their synaptic partners during development are not well understood. In a pursuit to obtain in-depth insights into these fundamental questions, we assess corticogenesis at unprecedented single cell resolution using the unique genetic strategy called MADM (Mosaic Analysis with Double Markers). MADM technology offers an unparalleled approach to visualize and concomitantly manipulate sparse clones and small subsets of genetically defined neurons in mice. Within the scope of the CIG project we used multidisciplinary experimental approaches including but not restricted to mouse genetic techniques and MADM, high resolution 4D live-imaging, and gene expression profiling. It was our goal to drive a research program with the following major objectives: 1) Determination of cortical neuron lineages by MADM; 2) Dissection of the molecular mechanisms of cortical neuronal migration and 3) Probing genomic imprinting, an epigenetic phenomenon, in cortex development. Together, these research directions have precipitated into significant conceptual progress regarding the fundamental cellular, molecular and epigenetic principles of cerebral cortex development. In brief, along objective 1) we have analyzed excitatory neuron genesis in the mouse neocortex using the MADM technique and could demonstrate that cortical projection neuron and glia genesis follows a defined, highly predictable deterministic program (Gao, Postiglione et al., 2014 Cell Vol 159(4):775-788). We next evaluated the underlying molecular mechanisms and thereby revealed novel functions of the Lgl1 gene in neural stem cells (Beattie et al., 2017 Neuron Vol 94(3):517-533). We are now following up along these new results and have generated novel MADM tools in order to pursue additional candidate gene analysis in the future to determine the mechanisms and principles controlling cortical neurogenesis. Within objective 2) we have deciphered the cell-autonomous and non-autonomous mechanisms controlling projection neuron migration (Hansen et al., in preparation). For objective 3) we have successfully established an experimental MADM-based platform to probe for genomic imprinting. Extensive bioinformatics analysis led to significant novel insights (Laukoter, Pauler et al., in preparation). Altogether, we have fully achieved the CIG project objectives. Ultimately, the results and advances along the CIG shall contribute to a deeper understanding of brain function; and why human brain development is so sensitive to the disruption of particular signaling pathways in pathological neurodevelopmental or psychiatric disorders.
The CIG was highly beneficial for the fellow in order to integrate into the European scientific community. Such integration was probably key for the successful execution of the project from a scientific point of view but also from a managerial side. The fellow established a dynamic research team which is very productive. In addition the fellow could secure substantial additional funding, including an HFSP program grant, NFB grant and most importantly an ERC consolidator grant which shall provide some financial stability for the future years. The fellow integrated very well at the host institute and will be evaluated for tenure soon. The fellow contributed to the graduate school of the host institute, established a teaching program and trained a great number of interns, graduate students, postdocs and technicians. Lastly, the fellow participated in many outreach activities, including the open campus day, the children summer camp and gave family lectures for the general public.