Further Development 14.5: Asymmetric Divisions: VRG Are a Notch above Par

Brain Growth

Another mechanism involved in determining the fate of cells derived from an asymmetrical division of a radial glial stem cell is how the apical protein Par-3 is distributed (Figure 1A). In general, Par-3 maintains the apical-basal polarity of cells. In the developing brain, Par-3 recruits a complex in the apical portion of the cell that can segregate cell-fate-inducing factors, such as Notch signaling proteins. In an asymmetrical division, one daughter cell receives more Par-3 protein than the other (Figure 1B). The daughter cell receiving more Par-3 develops high Notch signaling activity and remains a stem cell. The other daughter cell expresses high amounts of the Delta protein (recall that Delta is the Notch receptor) and becomes primed for neuronal differentiation (Bultje et al. 2009).

FIGURE 1 Asymmetrical division of radial glia mediated by Par-3 and Notch. (A) Schematic section of a chick embryo neural tube, showing the position of the nucleus and Par-3 protein in a radial glial cell as a function of the cell cycle. Mitotic cells are found near the inner surface of the neural tube, adjacent to the lumen. The dynamic distribution of Par-3 protein in these luminal stem cells regulates the synthesis of Notch signaling pathway components in the cell membrane of the daughter cells. At mitosis, Par-3 becomes localized primarily to one of the two daughter cells. That daughter cell will express high levels of Notch and remain a stem cell; the cell receiving less Par-3 will express less Notch and become a neural progenitor cell. (B) Fusing the Par-3 gene with GFP enables visualization of Par-3 protein movement during division, as seen here in the zebrafish embryonic hindbrain. Par-3 (bright green) is isolated primarily to the daughter cell on the left (arrowhead) after an asymmetrical division. As illustrated in (A), this cell will remain a stem cell. (A after R. S. Bultje et al. 2009. Neuron 63: 189–202; J. H.
Lui et al. 2011. Cell 146: 18–36.)

Developing Questions

It has been shown that the Hes family of Notch-transcriptional effectors exhibit oscillating periods of gene expression in vRG due to a negative feedback mechanism (see Chapters 4 and 17; Shimojo et al. 2008). It is intriguing to speculate about a model in which the number of Notch-Hes oscillations a vRG cell experiences might regulate its developmental fate for renewal, progenitor derivation, or differentiation (Paridaen and Huttner 2014).

Literature Cited

Bultje, R. S., D. R. Castaneda-Castellanos, L. Y. Jan, Y. N. Jan, A. R. Kriegstein and S. H. Shi. 2009. Mammalian Par3 regulates progenitor cell asymmetric division via notch signaling in the developing neocortex. Neuron 63: 189–202.
PubMed Link

Paridaen, J. T. and W. B. Huttner. 2014. Neurogenesis during development of the vertebrate central nervous system. EMBO Rep. 15: 351–364.
PubMed Link

Shimojo, H., T. Ohtsuka, and R. Kageyama. 2008. Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron 58: 52–64
PubMed Link

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