Abstract
The neurons of the mammalian brain are generated by progenitors dividing either at the apical surface of the ventricular zone (neuroepithelial and radial glial cells, collectively referred to as apical progenitors) or at its basal side (basal progenitors, also called intermediate progenitors). For apical progenitors, the orientation of the cleavage plane relative to their apical-basal axis is thought to be of critical importance for the fate of the daughter cells. For basal progenitors, the relationship between cell polarity, cleavage plane orientation and the fate of daughter cells is unknown. Here, we have investigated these issues at the very onset of cortical neurogenesis. To directly observe the generation of neurons from apical and basal progenitors, we established a novel transgenic mouse line in which membrane GFP is expressed from the beta-III-tubulin promoter, an early pan-neuronal marker, and crossed this line with a previously described knock-in line in which nuclear GFP is expressed from the Tis21 promoter, a pan-neurogenic progenitor marker. Mitotic Tis21-positive basal progenitors nearly always divided symmetrically, generating two neurons, but, in contrast to symmetrically dividing apical progenitors, lacked apical-basal polarity and showed a nearly randomized cleavage plane orientation. Moreover, the appearance of beta-III-tubulin–driven GFP fluorescence in basal progenitor-derived neurons, in contrast to that in apical progenitor-derived neurons, was so rapid that it suggested the initiation of the neuronal phenotype already in the progenitor. Our observations imply that (i) the loss of apical-basal polarity restricts neuronal progenitors to the symmetric mode of cell division, and that (ii) basal progenitors initiate the expression of neuronal phenotype already before mitosis, in contrast to apical progenitors.
Highlights
The stem and progenitor cells that generate the neurons of the mammalian central nervous system build up a polarized tissue, the wall of the neural tube, whose inner side faces the lumen of the neural tube and whose outer side contacts the basal lamina
To identify neurons generated by apical progenitors (APs) and basal progenitors (BPs) on live imaging, we generated a transgenic mouse line in which membraneanchored GFP is expressed under the control of the promoter of the mouse beta-III-tubulin gene (Tubb3), which is expressed in newborn neurons [28]
The value of 100 min corresponds to the mean ventricular zone (VZ) residence time of those BP daughter nuclei that were seen to eventually enter the neuronal layer. When both nuclei could be tracked in the VZ for longer than 100 min (9 of 18), we considered that the lack of entry into the neuronal layer might be significant, perhaps indicating a delayed onset of the neuronal phenotype
Summary
The stem and progenitor cells that generate the neurons of the mammalian central nervous system (here collectively referred to as neural progenitors) build up a polarized tissue, the wall of the neural tube, whose inner side faces the lumen of the neural tube and whose outer side contacts the basal lamina. This wall consists of neuroepithelial cells, the primary neural progenitors, which form the pseudostratified neuroepithelium. With the onset and progression of neurogenesis, additional neural progenitors appear, and the neural tube wall adopts a multi-celllayer architecture. Neural progenitors in the developing cerebral cortex can be classified into two principal groups depending on whether they undergo mitosis at the apical or basal side of the VZ. Neuroepithelial cells and the related cells they transform into with neurogenesis, the radial glial cells [4,6] and the recently described short neural precursors [7,8], undergo mitosis at the lumenal surface, which corresponds to their apical side; these cells will collectively be referred to as apical progenitors (APs). Aside from the site of mitosis, APs and BPs can be distinguished by the expression of distinct transcription factors, i.e. Pax and Tbr, respectively [12,13]
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