Oblique Radial Glial Divisions in the Developing Mouse Neocortex Induce Self-Renewing Progenitors outside the Germinal Zone That Resemble Primate Outer Subventricular Zone Progenitors

Abstract

Radial glia cells function as neural stem cells in the developing brain and generate self-renewing and differentiating daughter cells by asymmetric cell divisions. During these divisions, the apical process or basal process of the elongated epithelial structure is asymmetrically partitioned into daughter cells, depending on developmental contexts. However, in mammalian neurogenesis, the relationship between these subcellular structures and self-renewability is largely unknown. We induced oblique cleavages of radial glia cells to split the apical and basal processes into two daughters, and investigated the fate and morphology of the daughters in slice cultures. We observed that the more basal daughter cell that inherits the basal process self-renews outside of the ventricular zone (VZ), while the more apical daughter cell differentiates. These self-renewing progenitors, termed "outer VZ progenitors," retain the basal but not the apical process, as recently reported for the outer subventricular zone (OSVZ) progenitors in primates (Fietz et al., 2010; Hansen et al., 2010); to self-renew, they require clonal Notch signaling between sibling cells. We also found a small endogenous population of outer VZ progenitors in the mouse embryonic neocortex, consistent with a low frequency of oblique radial glia divisions. Our results describe the general role of the basal process in the self-renewal of neural progenitors and implicate the loss of the apical junctions during oblique divisions as a possible mechanism for generating OSVZ progenitors. We propose that mouse outer VZ progenitors, induced by oblique cleavages, provide a model to study both progenitor self-renewal and OSVZ progenitors.