The cerebral cortex is the largest area of the brain, involving remarkable neuronal diversity. Yet, the way in which functional cortical circuitry arises from neural stem cells (NSCs), in the developing neuroepithelium, remains unknown.

Radial glia progenitors (RGPs) are responsible for producing all neocortical projection neurons, certain glia, and establish the adult stem cell niche in the lateral ventricle. The Hippenmeyer group at the Institute of Science and Technology Austria, recently demonstrated the highly deterministic nature of RGP behaviour in the mammalian neocortex. In effect, RGPs transit through distinct cell states across different time windows. However, we do not know the cellular and molecular mechanisms which control RGP lineage progression through proliferation, neurogenesis and gliogenesis.

To obtain definitive insights into these fundamental questions we reassessed RGP lineage progression at unprecedented single cell and temporal resolution, using the unique MADM (Mosaic Analysis with Double Markers) technology which was developed in the Hippenmeyer group. MADM offers a genetic approach to visualize and concomitantly genetically manipulate single clones and small subsets of neurons.

We now focus on the functional genetic analysis of the PTEN singling pathway which is predicted to play a fundamental role in temporal RGP lineage progression since Pten mutations, in humans, result in cortical malformations including macrocephaly. We are interested in defining the role of Pten signaling in temporal stem cell lineage progression and dissect the relative contribution of cell-autonomous Pten signaling and cell-non-autonomous niche-derived cues in RGP lineage progression.

Together with the Urban group we will work to determine the function of Pten in gliogenesis and adult stem cells. In collaboration with the Kicheva group we will analyze neural stem cell lineage progression and Pten function in spinal cord progenitors.

In a joint effort with the Knoblich, Edenhofer and Tanaka groups, we hope to establish MADM technology in human organoid systems and the axolotl, to study temporal stem cell lineage tracing in human and regeneration models.

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