Olig2 and Hes regulatory dynamics during motor neuron differentiation revealed by single cell transcriptomics

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Abstract
During tissue development, multipotent progenitors differentiate into specific cell types in characteristic spatial and temporal patterns. We addressed the mechanism linking progenitor identity and differentiation rate in the neural tube, where motor neuron (MN) progenitors differentiate more rapidly than other progenitors. Using single cell transcriptomics, we defined the transcriptional changes associated with the transition of neural progenitors into MNs. Reconstruction of gene expression dynamics from these data indicate a pivotal role for the MN determinant Olig2 just prior to MN differentiation. Olig2 represses expression of the Notch signaling pathway effectors Hes1 and Hes5. Olig2 repression of Hes5 appears to be direct, via a conserved regulatory element within the Hes5 locus that restricts expression from MN progenitors. These findings reveal a tight coupling between the regulatory networks that control patterning and neuronal differentiation and demonstrate how Olig2 acts as the developmental pacemaker coordinating the spatial and temporal pattern of MN generation. How are the right types of cells produced in the right place, at the right time and in the correct numbers, in a developing tissue? One example of where progress has been made towards answering this question is the embryonic spinal cord. In this tissue, extracellular signals, such as the morphogen sonic hedgehog (Shh), control the pattern of generation of molecularly distinct sets of neural progenitors, from which different classes of motor neurons and interneurons are generated. Motor neurons differentiate at a much higher rate than the adjacent interneurons, and this ensures that more motor neurons than interneurons are generated and in an appropriate temporal sequence. To understand the mechanisms responsible for this phenomenon, we investigated the dynamics of the Shh-controlled gene regulatory network operating as motor neurons form from progenitors. We used these data to uncover the accompanying regulatory mechanisms, and this identified two functions for the transcription factor Olig2. First, Olig2 is essential for establishing motor neuron progenitor identity downstream of Shh signaling. Subsequently, Olig2 directly promotes neuronal differentiation in motor neuron progenitors by suppressing the expression of Hes genes, negative regulators of neuronal differentiation. Together, our findings reveal a tight coupling between the genetic networks that control patterning and neuronal differentiation in motor neuron progenitors and thereby explain their characteristic early and rapid rate of neuronal differentiation.
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