The ventricular-subventricular zone (V-SVZ), on the walls of the lateral ventricles, harbors the largest neurogenic niche in the adult mouse brain. Previous work has shown that neural stem/progenitor cells (NSPCs) in different locations within the V-SVZ produce different subtypes of new neurons for the olfactory bulb. The molecular signatures that underlie this regional heterogeneity remain largely unknown. Here, we present a single-cell RNA-sequencing dataset of the adult mouse V-SVZ revealing two populations of NSPCs that reside in largely non-overlapping domains in either the dorsal or ventral V-SVZ. These regional differences in gene expression were further validated using a single-nucleus RNA-sequencing reference dataset of regionally microdissected domains of the V-SVZ and by immunocytochemistry and RNAscope localization. We also identify two subpopulations of young neurons that have gene expression profiles consistent with a dorsal or ventral origin. Interestingly, a subset of genes are dynamically expressed, but maintained, in the ventral or dorsal lineages. The study provides novel markers and territories to understand the region-specific regulation of adult neurogenesis.
Keywords: adult neurogenesis; mouse; neuroblast; neuroscience; olfactory bulb; regenerative medicine; regional differences; single-cell sequencing; stem cell; stem cells.
Nerve cells, or neurons, are the central building blocks of brain circuits. Their damage, death or loss of function leads to cognitive decline. Neural stem/progenitor cells (NSPCs) first appear during embryo development, generating most of the neurons found in the nervous system. However, the adult brain retains a small subpopulation of NSPCs, which in some species are an important source of new neurons throughout life. In the adult mouse brain the largest population of NSPCs, known as B cells, is found in an area called the ventricular-subventricular zone (V-SVZ). These V-SVZ B cells have properties of specialized support cells known as astrocytes, but they can also divide and generate intermediate ‘progenitor cells’ called C cells. These, in turn, divide to generate large numbers of young ‘A cells’ neurons that undertake a long and complex migration from V-SVZ to the olfactory bulb, the first relay in the central nervous system for the processing of smells. Depending on their location in the V-SVZ, B cells can generate different kinds of neurons, leading to at least ten subtypes of neurons. Why this is the case is still poorly understood. To examine this question, Cebrián-Silla, Nascimento, Redmond, Mansky et al. determined which genes were expressed in B, C and A cells from different parts of the V-SVZ. While cells within each of these populations had different expression patterns, those that originated in the same V-SVZ locations shared a set of genes, many of which associated with regional specification in the developing brain. Some, however, were intriguingly linked to hormonal regulation. Salient differences between B cells depended on whether the cells originated closer to the top (‘dorsal’ position) or to the bottom of the brain (‘ventral’ position). This information was used to stain slices of mouse brains for the RNA and proteins produced by these genes in different regions. These experiments revealed dorsal and ventral territories containing B cells with distinct ‘gene expression’. This study highlights the heterogeneity of NSPCs, revealing key molecular differences among B cells in dorsal and ventral areas of the V-SVZ and reinforcing the concept that the location of NSPCs determines the types of neuron they generate. Furthermore, the birth of specific types of neurons from B cells that are so strictly localized highlights the importance of neuronal migration to ensure that young neurons with specific properties reach their appropriate destination in the olfactory bulb. The work by Cebrián-Silla, Nascimento, Redmond, Mansky et al. has identified sets of genes that are differentially expressed in dorsal and ventral regions which may contribute to regional regulation. Furthering the understanding of how adult NSPCs differ according to their location will help determine how various neuron types emerge in the adult brain.
© 2021, Cebrian-Silla et al.