Grant: Operating Grant

In many neurological and psychiatric disorder it is not clear which cell type is primarily affected. The present proposal attempts to define the neural stem cell lineage - the cellular lineage steps between the pluripotent cell of the blastocyst and mature neurons and glial cells. More specifically, we will investigate the mechanisms leading from the first embryonic neural cell (the primitive neural stem cell) to the definitive neural stem cells that are found later in embryogenesis and in the adult brain, thus making the identification of cell types affected in neurological and psychiatric disorders easier. Furthermore, we propose to study a rare population of quiescent primitive neural stem cells that persist into the adult brain, and appear to have the ability to reconstitute the definitive neural stem cell pool after the definitive pool has been removed. In addition, new signalling mechanisms enriched on the cell surfaces of primitive versus definitive neural stem cells will be tested for their abilities to specifically activate one of these two neural stem cell types, with potential clinical therapeutic implications. Finally, we will ask if damaged proteins and chromosomes containing older chromatids are selectively sorted to one of the two progeny of asymmetrically dividing stem cells. Moreover, in live video imaging and lineage reconstruction of single primitive or definitive neural stem cell clones will reveal if asymmetric segregation of these determinants affects the fates of the cells in these lineages.