Cell fate: Unlocking the right combination

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Helix-loop-helix (HLH) transcription factors determine both the position of multipotent neuronal progenitor cells and timing of differentiation.

During the development of the nervous system, multipotent progenitors differentiate into neurons, oligodendrocytes and astrocytes. Lineage specification is tightly regulated by both cell-intrinsic and cell-extrinsic factors, but little is known about how the timing and position of differentiation is determined. Masato Nakafuku and colleagues shed light on this issue by examining the spatial and temporal expression of patterning and helix-loop-helix (HLH) transcription factors, and their action on cell fate specification in the spinal cord.

Proneural HLH transcription factors, such as neurogenins (NGN1, 2 and 3) and MASH1, and inhibitory HLH factors — repressors of proneural gene transcription and activity such as members of the ID and HES families — have key roles in the specification of neurons and glia. However, their expression patterns do not directly correlate with the spatiotemporal pattern of neurogenesis and gliogenesis. In this study, the authors examined the effects of PAX6, OLIG2 and NKX2.2, also known as 'patterning' transcription factors because they specify the positional identity of multipotent progenitors in the spinal cord, on the ability of HLH factors to determine neuronal or glial fate.

The authors show that in the ventricular zone of the developing spinal cord, progenitors in the Pax6-, Olig2- and Nkx2.2-expressing regions also express neurogenins during neurogenesis. However, in the same regions, Mash1 expression was detected beyond the neurogenic period, suggesting a potential new role for MASH1 in gliogenesis. The onset of oligodendrogenesis differed between the three regions. In the Pax6-expressing region it correlated with loss of Pax6 expression in MASH1-positive cells. Interestingly, inhibitory HLHs were also found to be expressed before the onset of astrogenesis, a period that coincides with a decrease in the expression of patterning factors.

To examine the action of HLH and patterning factors on cell specification, the authors introduced specific combinations by retroviral infection into neurospheres derived from embryonic day 13.5 spinal cords, and found that all three patterning factors were able to bias the fate of multipotent progenitors. PAX6, OLIG2 and NKX2.2 suppressed the neurogenic effects of neurogenins, but had different effects on MASH1 — PAX6 promoted MASH1-induced neurogenesis, OLIG2 enhanced its oligodendrogenic effects and NKX2.2 was compatible with both of its activities. PAX6, OLIG2 and NKX2.2 were also found to prevent the differentiation of progenitors when co-expressed with Id1 and Hes1, suggesting that they can suppress the astrogenic activity of inhibitory HLH factors.

By genetically manipulating the temporal expression of HLH and patterning factors in mice, Nakafuku and colleagues were able to alter the timing of neuron and glia differentiation in vivo. They show that premature expression of Mash1 or loss of Pax6 stimulated oligodendrogenesis and the production of late-born neurons, indicating that PAX6 keeps the gliogenic activity of MASH1, and inhibitory HLH factors, in check until the onset of gliogenesis.

Together, these results suggest that patterning factors not only specify the positional identity of multipotent progenitors, but also that by modulating the activity of HLH transcription factors they have an important role in the timing of cell lineage specification. How these factors coordinate the genetic programmes required for neuronal differentiation and glial determination awaits further investigation.

Monica Hoyos Flight

References

Sugimori, M. et al. Combinatorial actions of patterning and HLH transcription factors in the spatiotemporal control of neurogenesis and gliogenesis in the developing spinal cord. Development 134, 1617–1629 (2007) | Article | PubMed |