Unraveling mouse striatal development from embryonic to postnatal stages

The embryonic striatal development is a complex orchestrated process driven by a pattern of gene expression at neuronal progenitors. The correct maturation of striatal projection neurons (SPNs) that populate the striatum depends on their coordinated differentiation and their posterior organization into the striatal cytoarchitecture. Single-cell analysis can shed light into the physiology and pathology of striatal development, currently hampered by the heterogeneity of neural progenitors and the lack of gene markers. Here, we define for the first time the differentiation trajectories of SPNs by analyzing single-cell transcriptomic data from embryonic striatal progenitors to postnatal cell maturation in mouse. To that end, we generated mouse sc/snRNA-seq data between embryonic stages E12.5 and postnatal 5 months. Through differential analysis we obtain cluster marker genes, resulting in new progenitor markers. We also analyze shifts in cell-type distribution throughout development and perform RNA velocity and cell fate analysis, allowing us to compute fate probabilities which we use to detect the branching point of the two main SPN lineages (indirect-iSPN and direct-dSPN pathways). In addition, we identify key regulators along the differentiation process through cell-type specific gene regulatory network (GRN) analysis. Lastly, we build a model using the learned GRNs that enables in silico perturbation analysis. Our results suggest an early lineage commitment of cells and showcase an in silico perturbation model that produces consistent results with previous experimental knock-out experiments. This model is particularly useful to model neurodegenerative pathologies where striatal development is damaged such as Huntington´s disease or autism.