A hallmark of mammalian brain evolution is cortical expansion, which reflects an increase in the number of cortical neurons established by the progenitor cell subtypes present and the number of their neurogenic divisions. Recent studies have revealed a new class of radial glia–like (oRG) progenitor cells in the human brain, which reside in the outer subventricular zone. Expansion of the subventricular zone and appearance of oRG cells may have been essential evolutionary steps leading from lissencephalic to gyrencephalic neocortex. Here we show that oRG-like progenitor cells are present in the mouse embryonic neocortex. They arise from asymmetric divisions of radial glia and undergo self-renewing asymmetric divisions to generate neurons. Moreover, mouse oRG cells undergo mitotic somal translocation whereby centrosome movement into the basal process during interphase precedes nuclear translocation. Our finding of oRG cells in the developing rodent brain fills a gap in our understanding of neocortical expansion.
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We thank A. Alvarez-Buylla, D. Lim, C. Harwell, W.P. Ge and L. Fuentealba for comments on the manuscript and members of the Kriegstein laboratory for discussions. We thank W. Walantus and Y.Y. Wang for mouse surgery and technical support and D.V. Hansen and J.H. Lui for ideas and discussion. We thank F. Gage (Salk Institute) for GFP-retrovirus reagents. This work was supported by grants from the Bernard Osher Foundation and the US National Institute of Neurological Disorders and Stroke (to A.R.K.).
The authors declare no competing financial interests.
Supplementary Figures 1–6, Supplementary Movies 1–11 (PDF 2168 kb)
This movie shows an example of mitotic somal translocation and oRG cell division. An oRG cell undergoes mitotic somal translocation and divides. The upper cell inherits the basal fiber whereas the lower cell rapidly extends a prominent process towards the ventricle. Images were acquired every 10 min and the play rate is seven frames per second. (AVI 20194 kb)
This movie shows interkinetic nuclear migration (INM) of RG cells in mouse neocortex. An RG cell undergoes INM and divides at the VZ surface. Images were acquired every 10 min and the play rate is seven frames per second. (AVI 4231 kb)
This movie shows an example of two IP cell divisions in situ. Two IP cells divide in situ without nuclear translocation. Images were acquired every 10 min and the play rate is seven frames per second. (AVI 6241 kb)
This movie shows an oRG cell that divides and generates a daughter neuron. An oRG cell undergoes mitotic somal translocation and divides. The apical daughter cell acquires neuronal morphology 40 h after division, and extends a leading process toward the pia. After acquiring a short trailing process, the bipolar daughter cell migrates rapidly to the cortical plate. Images were acquired every 30 min and the play rate is seven frames per second. (AVI 63370 kb)
This movie shows an example of an asymmetric oRG cell division that yields a daughter oRG cell and a daughter neuron. Cell fate was revealed by immunostaining with anti-Pax6 (progenitor marker) and anti-NeuN (neuronal marker) after 12h further culture following time-lapse imaging. (AVI 2048 kb)
This movie shows an example of oRG cells originating from RG cells. Two days after in-utero intra-ventricular retrovirus infection at E11.5, a GFP-labelled RG cell was monitored at 15-min intervals. Asymmetric division of the RG cell generates a self-renewed RG cell, which undergoes a second division. Another daughter cell undergoes mitotic somal translocation before mitosis, a defining feature of oRG cell behaviour. Images were acquired every 15 min and the play rate is seven frames per second. (AVI 4331 kb)
This movie shows centrosome behaviour in mitotic oRG cells. The centrosome is revealed by DsRedex-Centrin1. Frames were acquired every 10 min and the play rate is seven frames per second. (AVI 8160 kb)
This movie shows centrosome behaviour in mitotic RG cells. The centrosome is revealed by DsRedex-Centrin1. Frames were acquired every 10 min and the play rate is seven frames per second. (AVI 791 kb)
This movie shows centrosome behaviour in mitotic IP cells. The centrosome is revealed by DsRedex-Centrin1. Frames were acquired every 10 min and the play rate is seven frames per second. (AVI 2256 kb)
This movie shows interkinetic nuclear migration (INM) of a group of RG cells in mouse neocortex. The group of RG cell undergoes INM and divides at the VZ surface. Images were acquired every 10 min and the play rate is seven frames per second. (AVI 1323 kb)
This movie shows no oRG cells mitosis after purposely severing the apical processes of radial glial cells. We used a scalpel to remove the apical surface of the VZ in order to sever the apical processes of radial glial cells. This process disrupted INM and division of RG cells at the VZ surface and does not produce oRG-like cell mitosis. Images were acquired every 10 min and the play rate is seven frames per second. (AVI 901 kb)
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