Timing of the retinoid-signalling pathway determines the expression of neuronal markers in neural progenitor cells.

By culturing neural progenitor cells in the presence of retinoid receptor agonists, we have defined the components of the retinoid-signalling pathway that are important for the birth and maintenance of neuronal cells. We provide evidence that depending on the order and combination of retinoid receptors activated, different neuronal cells are obtained. Astrocytes and oligodendrocytes are predominantly formed in the presence of activated retinoic acid receptor (RAR) alpha, whereas motoneurons are formed when RARbeta is activated. We have looked at the regulation of two transcription factors islet-1/2 which are involved in neuronal development. We find that activated RARbeta up-regulates islet-1 expression, whereas activation of RARalpha can either act in combination with RARbeta signalling to maintain islet-1 expression or induce islet-2 expression in the absence of activated RARbeta. RARgamma cannot directly regulate islet-1/2 but can down-regulate RARbeta expression, which results in loss of islet-1 expression. We finally show that activated RARalpha is one of the final steps required for a mature motoneuron phenotype.