Neuronal Cell Fate

The McConnell lab is exploring the process of how young neurons become committeed to their normal fates in the cerebral cortex, a layered structure in which each layer contains neurons with strikingly similar morphologies and axonal connections. Because of the "birthday" of a cortical neuron predicts its final position and connections, we can examine the developmental potential of these cells by transplanting them into different-aged brains, which provide altered environmental cues for development. Our results indicate that, early in the cell cycle, embryonic progenitor cells are multipotent: their projeny change their normal fates and migrate to the host-specific cortical layer following transplantation. However, just prior to mitosis, cortical progenitors commit to producing the class of neurons typical of that birthdate. The committed neurons migrate to their cell-autonomous destination upon transplantation and form axonal connections appropriate for their birthday. To address the question of how neurons are actually generated from multipotent progenitor cells, we have begun to follow the process of cell division in living cortical slices using time-lapse confocal microscopy. Our results provide evidence for the existence of asymmetric cell divisions within the ventricular zone, and suggest that the plane of cleavage of a dividing progenitor cell may correlate with the subsequent decision of its daughters to reenter the cell cycle or differentiate into a postmitotic neuron. Notch1 protein is asymmetrically localized to the basal pole of mitotic progenitors, and appears to be differentially inherited in neurogenic divisions. Finally, we are exploring the expression patterns of a variety of genes that may play a role in specifying different types of neurons. For example, the homeodomain gene Otx1 (a vertebrate homolog of orthodenticle in Drosophila) is expressed specifically by a subset of deep-layer neurons and their progenitors; Otx1 is not expressed by upper layer neurons and is present at only very low levels in their precursors. These results raise the possibility that early and late progenitor cells may have distinct developmental potentials, a hypothesis that is supported by the results of tranplanting late progenitor cells into a younger brain environment.