Nenad Sestan

Obsessive–compulsive disorder (OCD) and chronic tic disorders (CTDs) are highly heritable. Rare mutations confer large risks for OCD and CTDs but only four high-confidence (hc) genes have been identified. Here we analyzed whole-exome sequencing data from 3,964 individuals with OCD, CTDs or both, including 2,418 trios. We found an excess in cases of de novo and rare protein-damaging mutations and identified 36 hc genes (false discovery rate < 0.1), including four previously identified hc genes ( CELSR3, CHD8, SCUBE1 and WWC1 ) and four genes that overlap with OCD genome-wide association study loci ( BRWD1 , CELSR3 , QRICH1 and SYNE1 ). Risk genes are shared among OCD, CTDs and other neurodevelopmental conditions. Transcriptomic and network analyses highlight mechanistic convergence and increased risk gene expression in postnatal cerebellum, prenatal and postnatal cortex and striatum. Dozens of large-effect OCD and CTD genes offer insights into pathogenesis and a path forward for illuminating pathophysiology and identifying novel treatment targets.

The cerebral cortex is organized along a dominant sensorimotor-to-association (S-A) axis, anchored by modality-specific primary sensorimotor areas at one end and transmodal association areas forming distributed networks that support abstract cognition at the other^1-11. The developmental mechanisms shaping this axis remain unclear^9-24. Here we present converging multispecies evidence supporting the multinodal induction-exclusion in network development (MIND) model, in which S-A patterning is governed by competing processes of induction and exclusion driven by two opposing transcriptomically defined programs. 'Pericentral' programs are induced around the frontotemporal poles, progress inwards toward the central regions of the undifferentiated neocortex and define higher-order association features. 'Central' programs are induced centrally through first-order sensorimotor thalamocortical inputs, establish primary areas and exclude pericentral programs. These conserved programs compete for space, resulting in compartmentalized expression of axon guidance, cell-cell adhesion, retinoic acid signalling, synaptogenesis, WNT signalling and autism-risk-associated genes. Notably, PLXNC1 and SEMA7A, a receptor-ligand pair representing pericentral and central programs, respectively, exhibit repulsive interactions between primary and higher-order association corticocortical axons. Induction and exclusion together establish an S-A organization in which primary areas emerge as focal islands within a broader ocean of distributed association networks. The MIND model provides a unifying framework for experimental, evolutionary and clinical phenomena, revealing induction and exclusion as antagonistic yet complementary principles shaping the S-A axis and processing hierarchies.

Here, to enable researchers to more fully harness the collective discovery potential of multiomic data in the public domain, we have assembled gene-level transcriptomic data from ~200 studies of neocortical development and in vitro models. Applying joint matrix decomposition to mouse, macaque and human data, we define transcriptome dynamics that are conserved across neocortical neurogenesis and identify a program that emerges in ventricular progenitors, is later expressed in neurogenic outer, or basal, radial glia of primates, but is limited to gliogenic precursors in the rodent. Decomposition of adult human neocortical data identified layer-specific signatures in excitatory neurons, enabling the charting of their developmental emergence and protracted maturation, which is in stark contrast to the early peaking expression of layer-defining transcription factors. Interrogation of data from cerebral organoids demonstrated that, although broad elements of in vivo development are recapitulated in vitro, many layer-specific transcriptomic programs in neuronal maturation are absent. We invite cell biologists without coding expertise to use NeMO Analytics in their research and to fuel it with their own emerging data at nemoanalytics.org/landing/neocortex.

Mammals have evolved a more complex brain, exemplified by the transformation of the single-layer dorsal cortex of excitatory projection neurons (ExNs) in ancestors into a multilayered cerebral neocortex^1-4 enriched with diverse intratelencephalic and extratelencephalic ExN subtypes^5-7, thereby establishing specialized projection systems that enhance brain connectivity and functionality^5-8. This is in contrast to modern reptiles and birds with single-layered or pseudolayered columnar organization of ExNs^4,9-12. However, the mechanisms underlying these mammalian-specific adaptations remain elusive. By comparing the landscape of gene expression and putative cis-regulatory elements (CREs) in mouse ExN subtypes and through cross-species examination, we identified mammalian-specific CREs, including a subset bound by the transcription factor ZBTB18 (also RP58, ZFP238 or ZNF238) and associated with genes defining intratelencephalic and extratelencephalic subtypes and connectivity, which have been implicated in intellectual disability and autism. Deletion of Zbtb18 in mouse ExNs dysregulated target gene expression, reduced molecular diversity, diminished cortico-spinal and callosal projections and increased intrahemispheric cortico-cortical association projections to the prefrontal cortex, thereby resembling non-mammalian brain. ZBTB18 binding motifs are highly enriched in callosally projecting intratelencephalic-biased putative CREs and show higher conservation specifically in mammals. This study uncovers critical components and mammalian-specific evolutionary adaptations within a regulatory node essential for neocortical ExN identity and connectivity.

The frontal lobe comprises the prefrontal association cortex (PFC), which supports complex cognition and goal-directed behavior, and the motor cortex (MC), which executes movement. A hallmark of primate brain evolution is PFC expansion accompanied by a posterior displacement of the MC. Retinoic acid (RA) signaling has emerged as a key regulator of PFC specification and expansion. However, the mechanisms that spatially confine RA signaling within the developing PFC, and the downstream RA-responsive gene networks, remain poorly understood. Here we defined an RA-associated gene regulatory network (RA-GRN) in the developing human PFC and identified MEIS2, which encodes a transcription factor linked to intellectual disability and autism spectrum disorder (ASD), as its key hub of this network. Conditional deletion of Meis2 in postmitotic cortical excitatory neurons in mice results in a partial respecification of prospective prefrontal association territories toward motor-like molecular and connectional features, highlighting a critical role of postmitotic neurons in establishing and maintaining cortical areal identities. Concomitant with Meis2 loss, the population of excitatory neurons expressing the RA-synthesizing enzyme ALDH1A3, and consequently RA signaling itself, is markedly reduced in the developing medial prefrontal cortex (mPFC). These findings revealed a conserved autoregulatory loop: RA -> MEIS2 -> ALDH1A3 -> RA that reinforces a PFC-enriched RA gradient and organizes the MC-PFC axis. Together, our findings reveal a postmitotic mechanism by which specific features of neuronal identity reinforce RA signaling to define key features of prefrontal and motor cortical territories, linking a classic morphogen to transcriptional identity, neural circuit formation and function, and potentially to psychiatric disorders.

The ability to spatially map multiple layers of omics information across developmental timepoints enables exploration of the mechanisms driving brain development¹, differentiation, arealization and disease-related alterations. Here we used spatial tri-omic sequencing, including spatial ATAC–RNA–protein sequencing and spatial CUT&Tag–RNA–protein sequencing, alongside multiplexed immunofluorescence imaging (co-detection by indexinng (CODEX)) to map dynamic spatial remodelling during brain development and neuroinflammation. We generated a spatiotemporal tri-omic atlas of the mouse brain from postnatal day 0 (P0) to P21 and compared corresponding regions with the human developing brain. In the cortex, we identified temporal persistence and spatial spreading of chromatin accessibility for a subset of layer-defining transcription factors. In the corpus callosum, we observed dynamic chromatin priming of myelin genes across subregions and identified a role for layer-specific projection neurons in coordinating axonogenesis and myelination. In a lysolecithin neuroinflammation mouse model, we detected molecular programs shared with developmental processes. Microglia exhibited both conserved and distinct programs for inflammation and resolution, with transient activation observed not only at the lesion core but also at distal locations. Overall, this study reveals common and differential mechanisms underlying brain development and neuroinflammation, providing a rich resource for investigating brain development, function and disease.

Neurodevelopmental disorders that cause cognitive, behavioural or motor impairments affect around 15% of children and adolescents worldwide¹, with diagnoses of profound autism and attention deficit hyperactivity disorder increasing in the USA and contributing to a major economic burden^2,3. Yet the origins and mechanisms of these conditions remain poorly understood, limiting progress in therapies. Comprehensive cell atlases of the developing human brain, alongside those of model organisms such as mice and non-human primates, are now providing high-resolution measures of gene expression, cell-type abundance and spatial distribution. In this Perspective, we highlight recent studies that have identified novel developmental cell populations, revealed conserved and divergent patterns of cell genesis, migration and maturation across species, and begun testing hypotheses that link them to processes ranging from transcriptional control of cell fate specification to the emergence of complex behaviours. We present remaining conceptual and technical challenges and provide an outlook on how further studies of human and mammalian brain development can empower a deeper understanding of neurodevelopmental and neuropsychiatric disorders. Future efforts expanding to additional developmental stages, including adolescence, as well as whole-brain, multimodal and cross-species integration, will yield new insights into how development shapes the brain. These atlases promise to serve as essential references for unravelling mechanisms of brain function and disease vulnerability, and for advancing precision medicine.