In:
Science, American Association for the Advancement of Science (AAAS), Vol. 377, No. 6614 ( 2022-09-30)
Abstract:
The dorsolateral prefrontal cortex (dlPFC) lies at the center of high-order cognition and complex social behaviors, which are highly derived traits in anthropoid primates—particularly in humans. RATIONALE The granular dlPFC represents an evolutionary specialization found only in anthropoid primates, and alterations in the molecular and cellular mechanisms underlying its intricate circuitry have been implicated in myriad neuropsychiatric diseases. However, little is known about the full repertoire of cell types in the primate dlPFC and how conserved these cell types are between human and other primate species. RESULTS We generated single-nucleus transcriptome data profiling more than 600,000 nuclei from the dlPFC of adult humans, chimpanzees, rhesus macaques, and common marmosets, thus spanning major primate phylogenetic groups. To study regulatory mechanisms underlying human-specific divergence, we generated single-nucleus multiome data (snATAC-seq and snRNA-seq) profiling the human dlPFC. Through cell clustering, marker gene expression, and integration with published multimodal and multispecies data we defined three levels of hierarchically organized taxonomy of transcriptomically defined neuronal, glial, and non-neural cell types in the four species, including four major cell classes, 29 subclasses and 114 subtypes. Most cell subtypes were conserved across the four species but we unraveled prominent species differences both at the molecular and cellular levels. We identified five cell subtypes detected in only a subset of species, including a layer (L) 2-3 intratelencephalic subtype absent in marmosets, an inhibitory neuron subtype exclusive to marmosets, and a microglial subtype detected only in humans. Cross-species comparisons of cell type proportions showed that L2-3 intratelencephalic neurons underwent substantial expansion in humans compared with other species as well as in Catarrhini as compared with marmosets. Gene expression entropy analysis revealed more transcriptomic heterogeneity among L2-3 intratelencephalic neurons in Catarrhini compared to marmosets. These results confirm and extend theories of primate cortical expansion. Within homologous cell subtypes across species, we identified prominent molecular changes. These are characterized by loss of expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine (including dopamine) biosynthesis, in the inhibitory neurons of chimpanzees that are homologous to TH-expressing inhibitory neurons in the other species studied. Among TH-expressing homologous cell subtypes in humans, macaques, and marmosets, we identified a human-specific posttranscriptional switch between the neuropeptide SST and TH, and the human-specific expression of genes involved in dopaminergic function. Through transcriptomic comparisons across the four primate species and immunohistochemistry across 51 mammal species, we found that the neuropsychiatric risk gene FOXP2 exhibited human-specific expression in microglia and primate-specific expression in L4 excitatory neurons. By integrating chromatin accessibility and gene coexpression, we identified cis-regulatory elements regulating FOXP2 expression and constructed FOXP2 regulatory networks including downstream targets mirroring the cell type- and species-specific FOXP2 expression patterns. CONCLUSION We produced a transcriptomic catalog of the primate dlPFC cell types, complemented with epigenomic characterization in the human dlPFC. Our analyses delineated cell type homology and transcriptomic conservation across species and identified species divergence at the molecular and cellular levels, as well as potential epigenomic mechanisms underlying these differences. Shared and species-divergent features were implicated in biological pathways and neuropsychiatric diseases. Our data may serve as a resource for future studies on prefrontal cortex function and disease. Transcriptomic taxonomy of the dlPFC in four anthropoid primates. (Top left) Homologous regions of the dlPFC dissected for snRNA-seq and sn-multiome analyses. (Top right) 114 hierarchically organized (dendrogram) transcriptomically defined cell subtypes distributed across the four species (bar plots; same color code as in the top left panel), with species-specific variations highlighted. (Bottom) Notable molecular changes across species featured by species-specific FOXP2 expression and the human-specific posttranscriptional switching between SST and TH.
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.abo7257
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2022
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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