Developmental trajectories of thalamic progenitors revealed by single-cell transcriptome profiling and Shh perturbation.

The thalamus is the principal information hub of the vertebrate brain, with essential roles in sensory and motor information processing, attention, and memory. The complex array of thalamic nuclei develops from a restricted pool of neural progenitors. We apply longitudinal single-cell RNA sequencing and regional abrogation of Sonic hedgehog (Shh) to map the developmental trajectories of thalamic progenitors, intermediate progenitors, and post-mitotic neurons as they coalesce into distinct thalamic nuclei. These data reveal that the complex architecture of the thalamus is established early during embryonic brain development through the coordinated action of four cell differentiation lineages derived from Shh-dependent and -independent progenitors. We systematically characterize the gene expression programs that define these thalamic lineages across time and demonstrate how their disruption upon Shh depletion causes pronounced locomotor impairment resembling infantile Parkinson's disease. These results reveal key principles of thalamic development and provide mechanistic insights into neurodevelopmental disorders resulting from thalamic dysfunction. [Display omitted] • Molecular signatures distinguish most thalamic nuclei prior to birth • Thalamic nuclei emerge from four distinct cell lineages • Defects in motor thalamic nuclei formation cause infantile Parkinson's disease Govek et al. describe the developmental trajectory of thalamic nuclei from Shh-dependent and -independent neural progenitors. They show that molecular signatures of thalamic neuronal subtypes can be distinguished prior to their aggregation into histologically distinct thalamic nuclei and that alterations in Shh cause neurodevelopmental disorders attributed to thalamic dysfunction. [ABSTRACT FROM AUTHOR]