Single-cell RNA Sequencing Uncovers A Close Relationship Between Differentiating Dopamine and Subthalamic Nucleus Neuronal Lineages

Stem cell engineering and grafting of mesencephalic dopamine (mesDA) neurons provides a promising strategy for brain repair in Parkinson’s disease (PD). However, essential refinement of differentiation protocols will require deeper interrogation of mesDA neuron lineage development. Here we studied neuronal development at the transcriptome-wide expression level by single-cell RNA sequencing of cells expressing the mesDA neuron transcription factor determinant Lmx1a. This approach resolved the differentiation of mesDA and neighboring neuronal lineages and revealed a remarkably close relationship between developing mesDA and subthalamic nucleus (STN) neurons. The combined ablation of Lmx1a and Lmx1b in mice disrupted both STN and mesDA neural development, while a distinct transcription factor set defined progenitors developing into STN neurons. Importantly, markers previously used to guide stem cell engineering into human mesDA neurons are shared between the two lineages. These results have important implications for stem cell engineering into mesDA neurons for cell replacement therapy in PD.