Making up your mind.

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Abstract
One of the key decisions that any neural stem cell faces is whether to commit to the neuronal or the glial lineage. The factors that regulate this commitment step are beginning to be identified, and the basic helix–loop– helix (bHLH) transcription factors have proved particularly important in this regard. These include the neurogenins (Ngn1 and Ngn2) and the mammalian achaete-scute homologue (Mash1), all of which promote neurogenesis. Indeed, Sun et al. recently showed that Ngn1 not only directly activates neurogenic genes, but also blocks the action of transcriptional complexes required for gliogenesis. In the developing cortex, knocking out Mash1 or Ngn2 causes misspecification of individual neuronal subsets, but does not lead to an overall reduction in neurogenesis. However, Ngn2; Mash1 double mutants show severe cortical defects, with increased and premature production of astrocytes at the expense of neurons. This implies that these two factors act in a redundant fashion to promote the neuronal fate. Now, as reported in Neuron, Nieto et al. have set out to establish the basis for this redundancy. Although the telencephalic expression domains of Ngn2 (dorsal) and Mash1 (ventral) are considered to be mutually exclusive, some low-level expression of Mash1 is seen in the cortex, and the gene is also upregulated in the Ngn2 knockout. Nieto et al. found that cortical progenitors are heterogeneous with respect to Ngn2 expression, prompting them to ask whether Ngn2 and Mash1 might normally act in different cell populations. To test this idea, they isolated cortical progenitors from Mash1 or Ngn2 knockout mice, sorted them on the basis of Ngn2 promoter activity and assessed their ability to generate neurons. Knocking out Ngn2 had little effect on the proportion of neurons that were generated, perhaps because of compensation by upregulation of Mash1. However, knocking out Mash1 led to a reduction in neurogenesis and a conversion of progenitors to astrocytic differentiation, both of which were particularly pronounced in the non-Ngn2-expressing fraction. So, the developing cortex contains a heterogeneous population of progenitor cells that differ at least in their expression of Ngn2. It remains to be seen whether there is also a separate Mash1-expressing progenitor population. This is a distinct possibility, as Mash1 is upregulated in the Ngn2 knockout cortex and, as Nieto et al. now show, its effects on neurogenesis seem to be most profound in cells that do not normally express Ngn2.

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