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A study presents a cross-species proteomic map of synapse development in neocortex and reveals that the human postsynaptic density assembly develops two to three times slower than that in macaques and mice.

A conserved gene regulatory network involving SOX4, SOX11 and TFAP2D shapes the development of excitatory neurons in ventrolateral pallium and their connectivity with the prefrontal cortex.

The implications of early telencephalic development in cortical disorders remain elusive. Here, the authors define risk gene dynamics and perturbation effects in neural stem cells, revealing vulnerability phases during early human corticogenesis.

A high-throughput technique has been developed to screen genes implicated in neurodevelopmental diseases in 3D cell cultures. It reveals a mechanism that might be involved in a rare disorder called microcephaly.

An innovative approach to analysing the functions and gene-expression profiles of neural stem cells in developing human and mouse brains sheds light on the differences — and similarities — between the two species. See Letter p.264

The authors identify deletions in a retinoic acid signalling responsive genetic element that leads to disproportionate increase of dendritic spines on neurons of the human prefrontal cortex.

A tri-omic atlas of the mouse brain from postnatal day 0 to P21 reveals that layer-specific projection neurons have a role in coordinating axonogenesis and myelination.

Osteocrin is a non-neuronal secreted protein in mice that has been evolutionarily repurposed to act as a neuronal development factor in primates.

SOX transcription factors converge on a cortex-specific enhancer to regulate the dynamic, cell-type-specific expression of Fezf2, a gene necessary for the formation of corticospinal system.

OrganEx—an extracorporeal pulsatile-perfusion system with cytoprotective perfusate for porcine whole-body settings—preserved tissue integrity, decreased cell death and restored selected molecular and cellular processes across multiple vital organs after 1 h of warm ischaemia in pigs.

Studies in mice, humans and macaques show that retinoic acid signalling has an important role in the development of the prefrontal cortex (PFC) in primates and may also underlie the evolutionary diversification of the PFC.

A specialized technology can restore and preserve microcirculation and cellular functions hours post-mortem in an isolated pig brain.

A comprehensive analysis of the cell-specific molecular regulatory mechanisms underlying post-traumatic stress disorder in the human prefrontal cortex.

Murat Gunel and colleagues report the identification of mutations in the laminin γ3 gene that cause complex bilateral occipital cortical gyration abnormalities in humans.

Multiplexed error-robust fluorescence in situ hybridization (MERFISH) together with deep-learning-based nucleus segmentation enabled the construction of a highly detailed and informative spatially resolved single-cell atlas of human fetal cortical development.

Difficult questions will be raised as models of the human brain get closer to replicating its functions, explain Nita A. Farahany, Henry T. Greely and 15 colleagues.

Recent studies integrating multi-omics data with cell atlases across development for brains of humans and model organisms are revealing conserved and divergent patterns of brain development at the molecular and cellular levels, and linking these to complex behavioural and neuropsychiatric phenotypes.

Cellular, transcriptomic and proteomic analyses of organoids derived from human induced pluripotent stem cells show that mTOR pathway hypoactivation is involved in two genetically distinct lissencephaly spectrum disorders.

Emerging perfusion technologies restore circulation and mitigate cell damage post ischaemia and reperfusion, showing promise for resuscitation medicine and organ transplantation. This Review explores cellular injury mechanisms, machine perfusion approaches and perfusate modifications for organ and whole-body recovery following circulatory cessation.

A spatially resolved transcriptional atlas of the mid-gestational developing human brain has been created using laser-capture microdissection and microarray technology, providing a comprehensive reference resource which also enables new hypotheses about the nature of human brain evolution and the origins of neurodevelopmental disorders.

Duy and Weise et al. combined human functional integrative genomics with mouse experimental biology to reveal a neuroprogenitor-based genetic subtype of human hydrocephalus with defective neurogenesis and altered brain–fluid biomechanics.

The cellular heterogeneity in brain obscures the identification of robust cellular regulatory networks. Here the authors integrate genome-wide chromosome conformation data from sorted neurons and glia, with transcriptomic and enhancer profiles, to characterize cell-type-specific gene regulatory landscapes in the human brain, and provide insights into cell-type-specific gene regulatory networks in brain disorders.

Astrocytes are important players in ischemic stroke. Here, the authors use single nuclei transcriptomics to characterise marmoset astrocytes following brain injury. At functional level, they show that NogoAexpressing astrocytes limit macrophage infiltration.

The largest whole-exome sequencing study of sporadic congenital hydrocephalus identities mutations associated with disrupted fetal neuro-gliogenesis as the primary pathophysiological event in a significant number of cases.

Autism genes converge in midfetal cortical co-expression networks, and chromatin regulators such as CHD8 are increasingly associated with autism spectrum disorder (ASD). Here the authors map CHD8 targets in developing brain, and find that CHD8 directly regulates other ASD risk genes during human neurodevelopment.

Quantitative mass spectrometry was used to produce a proteomic survey of postnatal human brain regions. Compared to matched RNA-seq, protein levels showed more regional variation, especially for membrane-associated proteins in the neocortex.

The optimal type or regional origin of stem cells for regenerative applications in the nervous system has not yet been established. Here the authors show that human neuroepithelial stem cells from the developing spinal cord, but not those from the developing cortex, show good host-graft interaction when transplanted to rodent models of spinal cord injury.

Laurent Fasano and colleagues identify TSHZ3 deletions in patients with autism spectrum disorder. Tshz3-mutant mice show functional changes at synapses established by cortical projection neurons and exhibit autism-like behavioral patterns.

The brain is particularly susceptible to injury after ischaemia; however, emerging evidence suggests that, under certain conditions, it may show more resilience. Daniele et al. review the effects of ischaemia on the brain and efforts to study and protect the post-ischaemic brain.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

The developmental Genotype-Tissue Expression (dGTEx) projects will catalogue and integrate gene expression, regulation and genetics data across 120 human donors from birth to adulthood with developmentally matched non-human primates, including 126 rhesus macaques and 72 common marmosets.

Recent research on disparate psychiatric disorders has implicated rare variants in genes involved in global gene regulation and chromatin modification, as well as many common variants located primarily in regulatory regions of the genome. Understanding precisely how these variants contribute to disease will require a deeper appreciation for the mechanisms of gene regulation in the developing and adult human brain. The PsychENCODE project aims to produce a public resource of multidimensional genomic data using tissue- and cell type–specific samples from approximately 1,000 phenotypically well-characterized, high-quality healthy and disease-affected human post-mortem brains, as well as functionally characterize disease-associated regulatory elements and variants in model systems. We are beginning with a focus on autism spectrum disorder, bipolar disorder and schizophrenia, and expect that this knowledge will apply to a wide variety of psychiatric disorders. This paper outlines the motivation and design of PsychENCODE.

Integrative anatomical, molecular, behavioral, and modeling evidence suggests that higher dopamine D1 receptor expression in prefrontal cortical parvalbumin neurons in marmosets likely contributes to their higher distractibility relative to macaques.

Single cell genome sequencing approaches have identified somatic copy number variants (CNVs) in human neurons, but small sample sizes (<100 neurons) have limited the power to find recurrent patterns such as CNV hotspots in a single individual. Here, the authors develop an approach to map CNVs in 2097 neurons from a neurotypical individual, finding that >10% neurons contain at least one somatic CNV, and enabling deeper investigation of these events.

Duffy et al. profiled mRNA translation in 73 human prenatal and adult cortex samples and identified thousands of previously unknown translation events, including small open reading frames that give rise to human-specific and/or brain-specific microproteins.

This Brain Somatic Mosaicism Network analysis of 283 cases of malformations of cortical development identifies 69 candidate and known genes in 76 patients. Single-nucleus RNA sequencing and mouse modeling implicate radial glia and daughter excitatory neurons.

SPLiT-seq single-nucleus RNA sequencing of the developing human cerebellum reveals cell-type complexities and prolonged maturation compared to mouse with important disease implications.

Rodin and Dou et al. characterized genome-wide somatic mutation in autistic and control brains, revealing that even unaffected individuals may possess dozens of brain somatic mutations and providing insight into the role of somatic mutation in autism.

This study presents a framework to evaluate rare and de novo variation from whole-genome sequencing (WGS). The work suggests that robust results from WGS studies will require large cohorts and strategies that consider the substantial multiple-testing burden.

Rare de novo single nucleotide variants in brain-expressed genes are found to be associated with autism spectrum disorders and to carry large effects.

Mapping disease loci that underlie putative Mendelian forms of malformations of cortical development is complicated by genetic heterogeneity, small family sizes and diagnostic classifications that may not reflect molecular pathogenesis. These authors use whole-exome sequencing to identify recessive mutations in WDR62 as the cause of a wide spectrum of severe cerebral cortical malformations. WDR62's nuclear localization to germinal neuroepithelia indicates that cortical malformations can be caused by events during progenitor proliferation and neurogenesis.