Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: A major site of neurogenesis

Abstract

Neurons of the mammalian CNS are thought to originate from progenitors dividing at the apical surface of the neuroepithelium. Here we use mouse embryos expressing GFP from the Tis21 locus, a gene expressed throughout the neural tube in most, if not all, neuron-generating progenitors, to specifically reveal the cell divisions that produce CNS neurons. In addition to the apical, asymmetric divisions of neuroepithelial (NE) cells that generate another NE cell and a neuron, we find, from the onset of neurogenesis, a second population of progenitors that divide in the basal region of the neuroepithelium and generate two neurons. Basal progenitors are most frequent in the telencephalon, where they outnumber the apically dividing neuron-generating NE cells. Our observations reconcile previous data on the origin and lineage of CNS neurons and show that basal, rather than apical, progenitors are the major source of the neurons of the mammalian neocortex.A ll neurons generated during the development of the mammalian CNS derive from neuroepithelial (NE) cells (see Supporting Text, which is published as supporting information on the PNAS web site). NE cells undergo three principal kinds of cell division, (i) symmetric, proliferative divisions (two NE cells) (see Supporting Text for terminology), (ii) asymmetric divisions (one NE cell, one neuron) and (iii) symmetric, differentiating divisions (two neurons) (1-6). It remains to be settled whether, at the very onset of neurogenesis, NE cells switch only to asymmetric division, or to both asymmetric and symmetric differentiating divisions.Real-time imaging studies of cells dividing at the apical surface of the neuroepithelium (7-9) and analyses of intrinsic cell fate determinants with a polarized distribution in mitotic NE cells (7, 10, 11) have provided evidence in support of the widely held view that during early neurogenesis, neurons are generated from NE cells by asymmetric rather than symmetric differentiating divisions (2,6,(12)(13)(14). In contrast, consistent with retroviral lineage tracing studies in vivo (5,(15)(16)(17)(18), analysis of the division patterns of isolated NE cells and their progeny has documented the coexistence, in vitro, of asymmetric and symmetric neurongenerating divisions of progenitors at the onset of neurogenesis (19-21). One possible explanation for this apparent discrepancy is the existence of neuronal progenitors other than the canonical NE cell dividing at the apical surface of the neuroepithelium.One of the problems in studying the divisions of NE cells that generate neurons has been the lack of a marker that allows one to distinguish between proliferating and neuron-generating NE cells and to identify the latter before they enter mitosis. Our group previously reported the first such marker, Tis21, an antiproliferative gene that within the neural tube is selectively expressed in neuron-generating, but not proliferating, NE cells, nor in neurons (22). Moreover, given that Ͼ95% of the newborn CNS neurons appear to inherit TIS21 protein from t...

The determination of projection neuron identity in the developing cerebral cortex

“…Direct evidence that the SVZ is a neurogenic zone has been derived from a recent series of elegant imaging experiments [19,20] in conjunction with related work from other labs [21][22][23]. Noctor and colleagues used time-lapse confocal time-lapse microscopy to track the behavior of individual GFP-labeled mitotic progenitors in the VZ and SVZ, and then to follow the behavior and fates of their daughter cells [19,24,25].…”

Neuronal stem cells in the central nervous system and in human diseases

“…However, the types of cells undergoing mitosis are still unclear. Recent studies indicate that throughout most of neurogenesis, other than an active role in VZ, RG cells also divide to populate the embryonic SVZ (Haubensak et al, 2004;Miyata et al, 2004;Noctor et al, 2004Noctor et al, , 2007b. RG cells usually undergo asymmetric cell division to yield a new RG cell and a neuron or an intermediate neural progenitor cell (IPC) (Fig.…”

“…RG cells usually undergo asymmetric cell division to yield a new RG cell and a neuron or an intermediate neural progenitor cell (IPC) (Fig. 1) (Haubensak et al, 2004;Noctor et al, 2004Noctor et al, , 2007b. IPC then divides symmetrically to generate two neurons or two additional IPCs (Wu and Cepko, 1993;Haubensak et al, 2004;Miyata et al, 2004;Noctor et al, 2004Noctor et al, , 2007a.…”

Emx2 and Foxg1 Inhibit Gliogenesis and Promote Neuronogenesis

“…Neuronal-restricted progenitors (NPs) include apical short neuronal precursors/''pin-like'' cells, within the VZ, and basal intermediate precursor cells, in both VZ and subventricular zone (SVZ). Bipotent glial-restricted progenitors (hereafter referred to as glial progenitors [GPs]) generate both astrocytes and oligodendrocytes [7][8][9][10][11][12][13][14][15].…”