Engineering neurogenesis

The mammalian cerebral cortex is often affected by neurodegenerative disease but lacks physiological neurogenesis. We could show that forced expression of lineage reprogramming factors can convert glial cells (astrocytes and oligodendrocyte precursors) into induced neurons in vitro and in vivo. These neurons develop functional properties such as the ability of firing action potentials. In a Wellcome Trust funded project we now aim at steering the conversion of glial cells into specific neuronal subtypes which may eventually allow a functional remodeling of diseased cortical circuits.

Lineage conversion of non-neuronal cells into induced neurons is a fascinating process. We could reprogram pericytes isolated from the adult human brain into functional induced neurons by forced expression of the transcription factors Ascl1 and Sox2. Now we employ single cell RNA sequencing technology to determine whether lineage reprogramming occurs via the direct conversion of a terminally differentiated cell into another, or involves a trajectory comprising stem cell-like states along the reprogramming trajectory.

The adult mammalian brain contains few neurogenic niches such as the dentate gyrus of the hippocampus and the subventricular zone lining the lateral ventricle. These niches harbor neural stem cells that give rise to new neurons throughout life. These neurons in turn integrate into the pre-existing neural circuitry. We are interested in understanding what determines the rate of neurogenesis as well as gliogenesis in these niches. Finally, we are also fascinated by the question how newly generated neurons functionally integrate. Towards this we have adopted a rabies virus tracing technique which allows for identifying presynaptic partners of new neurons and how presynaptic input becomes remodeled over time and under different environmental conditions.