INTRODUCTION The brain is responsible for cognition, behavior, and much of what makes us uniquely human. The development of the brain is a highly complex process, and this process is reliant on precise regulation of molecular and cellular events grounded in the spatiotemporal regulation of the transcriptome. Disruption of this regulation can lead to neuropsychiatric disorders. RATIONALE The regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types. Understanding the etiology of neuropsychiatric disorders requires knowledge not just of endpoint differences between healthy and diseased brains but also of the developmental and cellular contexts in which these differences arise. Moreover, an emerging body of research indicates that many aspects of the development and physiology of the human brain are not well recapitulated in model organisms, and therefore it is necessary that neuropsychiatric disorders be understood in the broader context of the developing and adult human brain. RESULTS Here we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood. We observed a widespread transcriptomic transition beginning during late fetal development and consisting of sharply decreased regional differences. This reduction coincided with increases in the transcriptional signatures of mature neurons and the expression of genes associated with dendrite development, synapse development, and neuronal activity, all of which were temporally synchronous across neocortical areas, as well as myelination and oligodendrocytes, which were asynchronous. Moreover, genes including MEF2C , SATB2 , and TCF4 , with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity. CONCLUSION We generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease. Spatiotemporal dynamics of human brain development and neuropsychiatric risks. Human brain development begins during embryonic development and continues through adulthood (top). Integrating data modalities (bottom left) revealed age- and cell type–specific properties and global patterns of transcriptional dynamics, including a late fetal transition (bottom middle). We related the variation in gene expression (brown, high; purple, low) to regulatory elements in the fetal and adult brains, cell type–specific signatures, and genetic loci associated with neuropsychiatric disorders (bottom right; gray circles indicate enrichment for corresponding features among module genes). Relationships depicted in this panel do not correspond to specific observations. CBC, cerebellar cortex; STR, striatum; HIP, hippocampus; MD, mediodorsal nucleus of thalamus; AMY, amygdala.
Abstract Autism spectrum disorder (ASD) represents a major mental health problem with estimates of prevalence ranging from 1/500 to 1/2000. While generally recognized as developmental in origin, little to nothing is certain about its etiology. Currently, diagnosis is made on the basis of a variety of early developmental delays and/or regressions in behavior. There are no universally agreed upon changes in brain structure or cell composition. No biomarkers of any type are available to aid or confirm the clinical diagnosis. In addition, while estimates of the heritability of the condition range from 60 to 90%, as of this writing no disease gene has been unequivocally identified. The prevalence of autism is three‐ to four‐fold higher in males than in females, but the reason for this sexual dimorphism is unknown. In light of all of these ambiguities, a proposal to discuss potential animal models may seem the heart of madness. However, parsing autism into its individual genetic, behavioral, and neurobiological components has already facilitated a ‘conversation’ between the human disease and the neuropathology and biochemistry underlying the disorder. Building on these results, it should be possible to not just replicate one aspect of autism but to connect the developmental abnormalities underlying the ultimate behavioral phenotype. A reciprocal conversation such as this, wherein the human disease informs on how to make a better animal model and the animal model teaches of the biology causal to autism, would be highly beneficial.
Abstract The ventrolateral pallial (VLp) excitatory neurons in the claustro-amygdalar complex and piriform cortex (PIR; which forms part of the palaeocortex) form reciprocal connections with the prefrontal cortex (PFC), integrating cognitive and sensory information that results in adaptive behaviours 1–5 . Early-life disruptions in these circuits are linked to neuropsychiatric disorders 4–8 , highlighting the importance of understanding their development. Here we reveal that the transcription factors SOX4, SOX11 and TFAP2D have a pivotal role in the development, identity and PFC connectivity of these excitatory neurons. The absence of SOX4 and SOX11 in post-mitotic excitatory neurons results in a marked reduction in the size of the basolateral amygdala complex (BLC), claustrum (CLA) and PIR. These transcription factors control BLC formation through direct regulation of Tfap2d expression. Cross-species analyses, including in humans, identified conserved Tfap2d expression in developing excitatory neurons of BLC, CLA, PIR and the associated transitional areas of the frontal, insular and temporal cortex. Although the loss and haploinsufficiency of Tfap2d yield similar alterations in learned threat-response behaviours, differences emerge in the phenotypes at different Tfap2d dosages, particularly in terms of changes observed in BLC size and BLC–PFC connectivity. This underscores the importance of Tfap2d dosage in orchestrating developmental shifts in BLC–PFC connectivity and behavioural modifications that resemble symptoms of neuropsychiatric disorders. Together, these findings reveal key elements of a conserved gene regulatory network that shapes the development and function of crucial VLp excitatory neurons and their PFC connectivity and offer insights into their evolution and alterations in neuropsychiatric disorders.
