THE CODING AND NON-CODING TRANSCRIPTOME OF THE HUMAN FETAL STRIATUM FROM A SINGLE-CELL PERSPECTIVE

The human brain is a tissue of vast complexity in terms of the cell types it comprises. Understanding how this complexity arises requires a deep understanding of how neuronal patterning progresses at the single cell level. Previous studies have concentrated on cell fate decisions during cortical development but little is known about how the lateral ganglionic eminences (LGE) develops and gives rise to the different cell populations of the striatum. Conventional approaches to classify cell types in this area have been limited to exploring relatively few markers and therefore have provided a narrow characterization of any given cell type. Furthermore, most studies have bounded their inquiries to protein-coding genes and have not investigated the role of lncRNAs that have been shown to have a high cell and tissue specificity. Taking these aspects under consideration, here we combined bulk RNA-seq and single-cell RNA-seq to decode an unambiguous gene signature of the striatum and reveal how neural progenitors of this domain are able to differentiate at the single cell level. In particular, we deeply profiled the LGE and the surrounding neocortex and medial ganglionic eminences (MGE), from 7 to 20 postconceptional weeks (pcw), and performed de novo lncRNAs analysis that enabled us to define the first dictionary of novel lincRNAs for these areas. Furthermore, this analysis led to the establishment of a unique gene signature for the three different regions. Subsequently, we performed single-cell RNA-seq of the LGE at 7pcw that unravelled a plethora of different cell populations of the LGE. Pseudotemporal ordering of these cells uncovered the first developmental trajectory of striatal neurons and how they transition from early progenitors to mature medium spiny neuron (MSNs) and their coding and non-coding transcriptional signature. This array of cells will shortly be complemented by another batch of single-cell libraries from later time points (9-11pcw) that will be used to full characterize the early steps of neural ramifications that lead to the generation of the human striatum. The relevance of the approach relies on the availability of extremely rare human fetal samples combined with the most revolutionary RNA sequencing technologies and highly elaborate computational tools that enable the investigation of a brain region, the striatum, whose development is poorly understood and which plays a major role in human brain physiology and pathology.