Mouse embryonic stem cells as a new discovery tool in neurobiology

As mouse embryonic stem (ES) cells can be propagated in vitro in unlimited quantities and manipulated to generate homogenous populations of progenitor cells, they represent an attractive system to investigate questions that have been difficult to study in the developing mammalian nervous system. Here, we tested the differentiation potential of ES cell-derived progenitors that have the identity of radial glial (RG) cells, a population of cells that produce large numbers of neurons in the embryonic central nervous system of vertebrates. We implanted these cells into the neural tube of the chick embryo and examined their fate days later. The results indicate that the developmental potential of RG cells is restricted and they can only generate cell types that are expected from their developmental history. Since ES cells are accessible for genetic manipulations, we also investigated the role of molecules involved in neuronal development in genetically-modified ES cell-derived neurons. Specifically, we tested the effects of preventing the downregulation of the receptor for neurotrophins p75NTR during neuronal differentiation. This maneuver led first to the degeneration of all the neuronal processes (axons and dendrites), and to the later demise of the neuronal cell bodies. We found that the degeneration of these different neuronal compartments depends on distinct molecular mechanisms. In addition, we identified the endogenous lectin Galectin-1 as a player in the degeneration of neurons. Our results suggest that Galectin-1 acts as an effector of neuronal degeneration downstream of p75NTR, both in vitro and in vivo. Together, the experiments presented here illustrate the advantages of working with homogenous cell populations derived from ES cells.