Dividing destiny

During development, the mitosis of stem and progenitor cells can give rise to two daughter cells with different fates. It is thought that uneven distribution of crucial intracellular signalling molecules during mitosis has an important role in this asymmetric cell fate determination. Now, a study published in Neuron reports a novel mechanism whereby unequal distribution of growth factor receptors during mitosis can result in two daughter cells with different environmental responsiveness and, therefore, different fates.

As the level of epidermal growth factor receptors (EGFRs) can influence the fate choice of cortical progenitor cells (CPCs) — overexpression at mid-gestation pushes cells into the astrocyte lineage at the expense of neuron formation — Sun and colleagues investigated how EGFR might be distributed during mitosis of these progenitors. They observed that, in brain sections from mouse embryos, EGFR expression varied considerably between pairs of daughter cells in 22% of dividing EGFR-positive CPCs.

The authors then plated CPCs in culture so that individual daughter cells could be easily traced and their EGFR expression studied. In vitro, some pairs of dividing CPCs showed an asymmetric distribution of EGFR, which resulted in one cell having high levels of EGFR expression (EGFR^high) and the other having almost none (EGFR^low). EGFR^high daughter cells showed much higher proliferative ability in response to EGF, and could migrate a greater distance towards EGF than their EGFR^lowcounterparts, which indicates that the sibling progenitors with different EGFR levels are functionally distinct.

If the expression of EGFR can affect the cell fate choice of cortical progenitors, do EGFR^high and EGFR^lowdaughter cells acquire different fates? Interestingly, most EGFR^high daughter cells expressed RC2, the marker for radial glia, and some of these went on to express GLAST, the marker for astrocytes. This was consistent with the observation that, in embryonic mouse brains, EGFR was colocalized with RC2 in CPCs with radial morphology. Contrastingly, EGFR^low daughter cells did not express either RC2 or GLAST, but expressed OLIG1 and OLIG2, which are early transcription factors that are involved in neuronal and oligodendrocyte differentiation. When cultured for a longer period of time, many of these EGFR^low cells expressed the oligodendrocyte marker NG2.

To understand exactly how astrocytes and oligodendrocytes are generated in culture over time, Sun et al. recorded single embryonic CPCs using time-lapse microscopy. At various stages of differentiation, clones were stained for EGFR expression and markers of neurons, astrocytes and oligodendrocytes. In this way, 'family trees' of individual CPCs were constructed and the origin of each progeny traced. This stringent lineage-tracing assay confirms the results of expression studies and indicates that asymmetric distribution of EGFR in CPCs is important for divergence, consistent with the EGFR^high and EGFR^low daughter cells giving rise to astrocyte and oligodendrocyte lineages, respectively.

These findings provide new insight into how neural cell diversity can be generated. It will be interesting to see whether asymmetric distribution of growth factor receptors is crucial for cell fate determination in other lineages. Furthermore, when one daughter cell inherits an excessive amount of receptors that are important for regulating proliferation, a mechanism for the derivation of cancerous cells might be formed.