Immunolabelling of OLIG2 (green) stains the nuclei of pMN cells in the ventral neural tube of an embryonic day 3.5 chick embryo. NGN2 (red) is detected in the nuclei of many cells in the neural tube, but is heterogenously expressed by pMN cells (yellow double labelling). The relative balance in OLIG2 and NGN2 levels is believed to be an important determinant for directing pMN cells to produce motor neurons (high NGN2) or oligodendrocytes (low NGN2). Image courtesy of S. Pfaff, Salk Institute, La Jolla, California, USA.

It is well known that the pMN progenitor domain of the embryonic ventral spinal cord gives rise first to motor neurons and later to oligodendrocytes, but how this dual role is accomplished is poorly understood. In a recent report in Genes and Development, Lee and colleagues shed new light on the molecular mechanisms that control the fate of progenitor cells in this region.

The basic helix–loop–helix (bHLH) transcription factors OLIG2 and neurogenin 2 (NGN2) are co-expressed in pMN cells that are not yet committed to an oligodendrocyte or motor neuron fate. Subsequently, OLIG2 is downregulated in cells that differentiate as motor neurons, whereas NGN2 is downregulated in cells that become oligodendrocytes. Previous findings have indicated that OLIG2 initially renders cells competent to enter the motor neuron lineage, by inducing the expression of factors such as NGN2 and LHX2. However, Lee et al. show that the continued expression of OLIG2 inhibits the post-mitotic development of motor neurons.

The authors showed that constitutive expression of OLIG2 throughout the dorsoventral axis of the neural tube in chick embryos caused a profound reduction in the generation of motor neurons. They also found that OLIG2 could prevent NGN2 from inducing neuronal differentiation in mouse teratocarcinoma cells. These findings prompted the authors to investigate how the activities of NGN2 and OLIG2 might be balanced to coordinate the generation of motor neurons and oligodendrocytes in the pMN domain.

One important clue came from the observation that in the wild-type chick neural tube, there was considerable heterogeneity between individual pMN cells with regard to NGN2 and OLIG2 expression levels. The relative levels of the two factors in any given cell were crucial for determining that cell's fate — cells that expressed relatively high levels of NGN2 differentiated as motor neurons, whereas cells that expressed relatively high levels of OLIG2 remained in a multipotent progenitor state.

To investigate the molecular basis of the antagonistic actions of OLIG2 and NGN2, Lee et al. investigated their effects on the expression of Hb9, a gene that is involved in motor neuron differentiation. They found that OLIG2 and NGN2 both bind to E-box regulatory elements in the Hb9 motor neuron-specific enhancer. NGN2, in a complex with the bHLH factor E47, activates Hb9 expression, whereas OLIG2 functions as a repressor. OLIG2 seems to prevent NGN2 from activating Hb9 in two ways — by binding to NGN2 itself and sequestering it away from the gene, and by competing to bind to the E-box elements.

So, by maintaining OLIG2 and NGN2 at heterogeneous levels among cells of the pMN domain, the embryo can allow one population of cells to differentiate as motor neurons, while keeping a multipotent progenitor population in reserve for the later generation of oligodendrocytes. The question of how this heterogeneity is established and maintained will no doubt provide an important challenge for future investigations.