An atlas of cortical arealization identifies dynamic molecular signatures

Abstract

The human brain is subdivided into distinct anatomical structures, including the neocortex, which in turn encompasses dozens of distinct specialized cortical areas. Early morphogenetic gradients are known to establish early brain regions and cortical areas, but how early patterns result in finer and more discrete spatial differences remains poorly understood1. Here we use single-cell RNA sequencing to profile ten major brain structures and six neocortical areas during peak neurogenesis and early gliogenesis. Within the neocortex, we find that early in the second trimester, a large number of genes are differentially expressed across distinct cortical areas in all cell types, including radial glia, the neural progenitors of the cortex. However, the abundance of areal transcriptomic signatures increases as radial glia differentiate into intermediate progenitor cells and ultimately give rise to excitatory neurons. Using an automated, multiplexed single-molecule fluorescent in situ hybridization approach, we find that laminar gene-expression patterns are highly dynamic across cortical regions. Together, our data suggest that early cortical areal patterning is defined by strong, mutually exclusive frontal and occipital gene-expression signatures, with resulting gradients giving rise to the specification of areas between these two poles throughout successive developmental timepoints.

Cortical Cartography: Mapping Arealization Using Single-Cell Omics Technology

“…Molecular signals within the cortex and those derived from extrinsic subcortical sources likely collaborate or compete with one another to generate molecular distinctions between cell types through developmental time. This diverse tapestry of transcriptional profiles may then underlie the presence of both discrete differences and continuous gradients of variation found between human cortical areas (Nowakowski et al, 2017;Li et al, 2018;Zhu et al, 2018;Bhaduri et al, 2021;Yao et al, 2021). This mixture of discrete and graded transcriptomic boundaries may be dynamic throughout development: interareal transcriptional states exhibit robust divergence prenatally, become more similar in infancy and childhood, and exhibit robust differences again in adolescence and onward (Li et al, 2018;Zhu et al, 2018).…”

“…More recent developmental and adult scRNA-seq studies have refined this theory, as the comparison of more cortical areas and the integration of molecular and connectivity profiles point to a continuum of cell types both within and across adult cortical areas. These studies have revealed that in both the developing and adult cortex, neighboring cortical areas have overlapping transcriptomic features that become increasingly distinct with greater spatial distance (Bhaduri et al, 2021;Yao et al, 2021). For example, the posterior-high to anteriorlow gradient marker gene NR2F1 is expressed at higher levels and in more cells in the posteriorly located V1 compared to the PFC (Bhaduri et al, 2021).…”

“…These studies have revealed that in both the developing and adult cortex, neighboring cortical areas have overlapping transcriptomic features that become increasingly distinct with greater spatial distance (Bhaduri et al, 2021;Yao et al, 2021). For example, the posterior-high to anteriorlow gradient marker gene NR2F1 is expressed at higher levels and in more cells in the posteriorly located V1 compared to the PFC (Bhaduri et al, 2021). However, NR2F1 expression is also enriched in the temporal and parietal lobes proximal to V1 and gradually decreases along the posterior to the anterior axis (Bhaduri et al, 2021).…”

“…For example, the posterior-high to anteriorlow gradient marker gene NR2F1 is expressed at higher levels and in more cells in the posteriorly located V1 compared to the PFC (Bhaduri et al, 2021). However, NR2F1 expression is also enriched in the temporal and parietal lobes proximal to V1 and gradually decreases along the posterior to the anterior axis (Bhaduri et al, 2021). Therefore, functionally discrete areas may arise from subtle transcriptional differences that lay the foundation for phenotypic differences found among the cortex.…”

“…This mixture of discrete and graded transcriptomic boundaries may be dynamic throughout development: interareal transcriptional states exhibit robust divergence prenatally, become more similar in infancy and childhood, and exhibit robust differences again in adolescence and onward (Li et al, 2018;Zhu et al, 2018). More refined single-cell transcriptomic datasets encompassing a greater number of cells, areas, and individuals showed that areal identities are also highly dynamic throughout neuronal differentiation, even though they remain most distinct at the PFC and V1, located at opposite poles of the cortex (Bhaduri et al, 2021). Taken together, these datasets reinforce the hypothesis that subtle but dynamic gene expression gradients in prenatal cortical progenitors become increasingly organized during cortical differentiation to give rise to areas with discrete neuronal subtypes and functionality.…”