SummaryHere we report the generation and analysis of genome-wide exon-level transcriptome data from 16 brain regions comprising the cerebellar cortex, mediodorsal nucleus of the thalamus, striatum, amygdala, hippocampus, and 11 areas of the neocortex. The dataset was generated from 1,340 tissue samples collected from one or both hemispheres of 57 postmortem human brains, spanning from embryonic development to late adulthood and representing males and females of multiple ethnicities. We also performed genotyping of 2.5 million SNPs and assessed copy number variations for all donors. Approximately 86% of protein-coding genes were found to be expressed using stringent criteria, and over 90% of these were differentially regulated at the whole transcript or exon level across regions and/or time. The majority of these spatiotemporal differences occurred before birth, followed by an increase in the similarity among regional transcriptomes during postnatal lifespan. Genes were organized into functionally distinct co-expression networks, and sex differences were present in gene expression and exon usage. Finally, we demonstrate how these results can be used to profile trajectories of genes associated with neurodevelopmental processes, cell types, neurotransmitter systems, autism, and schizophrenia, as well as to discover associations between SNPs and spatiotemporal gene expression. This study provides a comprehensive, publicly available dataset on the spatiotemporal human brain transcriptome and new insights into the transcriptional foundations of human neurodevelopment.

Successive ion layer adsorption and reaction (SILAR) originally developed for the deposition of thin films on solid substrates from solution baths is introduced as a technique for the growth of high-quality core/shell nanocrystals of compound semiconductors. The growth of the shell was designed to grow one monolayer at a time by alternating injections of air-stable and inexpensive cationic and anionic precursors into the reaction mixture with core nanocrystals. The principles of SILAR were demonstrated by the CdSe/CdS core/shell model system using its shell-thickness-dependent optical spectra as the probes with CdO and elemental S as the precursors. For this reaction system, a relatively high temperature, about 220-240 degrees C, was found to be essential for SILAR to fully occur. The synthesis can be readily performed on a multigram scale. The size distribution of the core/shell nanocrystals was maintained even after five monolayers of CdS shell (equivalent to about 10 times volume increase for a 3.5 nm CdSe nanocrystal) were grown onto the core nanocrystals. The epitaxial growth of the core/shell structures was verified by optical spectroscopy, TEM, XRD, and XPS. The photoluminescence quantum yield (PL QY) of the as-prepared CdSe/CdS core/shell nanocrystals ranged from 20% to 40%, and the PL full-width at half-maximum (fwhm) was maintained between 23 and 26 nm, even for those nanocrystals for which the UV-vis and PL peaks red-shifted by about 50 nm from that of the core nanocrystals. Several types of brightening phenomena were observed, some of which can further boost the PL QY of the core/shell nanocrystals. The CdSe/CdS core/shell nanocrystals were found to be superior in comparison to the highly luminescent CdSe plain core nanocrystals. The SILAR technique reported here can also be used for the growth of complex colloidal semiconductor nanostructures, such as quantum shells and colloidal quantum wells.

SUMMARY Our understanding of the evolution, formation, and pathological disruption of human brain circuits is impeded by a lack of comprehensive data on the developing brain transcriptome. Thus, we have undertaken whole-genome, exon-level expression analysis of thirteen regions from left and right sides of the mid-fetal human brain, finding 76% of genes to be expressed, and 44% of these to be differentially regulated. These data reveal a large number of specific gene expression and alternative splicing patterns, as well as co-expression networks, associated with distinct regions and neurodevelopmental processes. Of particular relevance to cognitive specializations, we have characterized the transcriptional landscapes of prefrontal cortex and perisylvian speech and language areas, which exhibit a population-level global expression symmetry. Finally, we show that differentially expressed genes are more frequently associated with human-specific evolution of putative cis-regulatory elements. Altogether, these data provide a wealth of novel biological insights into the complex transcriptional and molecular underpinnings of human brain development and evolution.

The polarity and adhesion of radial glial cells (RGCs), which function as progenitors and migrational guides for neurons, are critical for morphogenesis of the cerebral cortex. These characteristics largely depend on cadherin-based adherens junctions, which anchor apical end-feet of adjacent RGCs to each other at the ventricular surface. Here, we show that mouse numb and numb-like are required for maintaining radial glial adherens junctions. Numb accumulates in the apical end-feet, where it localizes to adherens junction-associated vesicles and interacts with cadherins. Numb and Numbl inactivation in RGCs decreases proper basolateral insertion of cadherins and disrupts adherens junctions and polarity, leading to progenitor dispersion and disorganized cortical lamination. Conversely, overexpression of Numb prolongs RGC polarization, in a cadherin-dependent manner, beyond the normal neurogenic period. Thus, by regulating RGC adhesion and polarity, Numb and Numbl are required for the tissue architecture of neurogenic niches and the cerebral cortex.

The human cerebral cortex depends for its normal development and size on a precisely controlled balance between self-renewal and differentiation of diverse neural progenitor cells. Specialized progenitors that are common in humans, but virtually absent in rodents, called ‘outer radial glia’ (ORG), have been suggested to be crucial to the evolutionary expansion of the human cortex. We combined progenitor subtype-specific sorting with transcriptome-wide RNA-sequencing to identify genes enriched in human ORG, which included targets of the transcription factor Neurogenin and previously uncharacterized, evolutionarily dynamic long noncoding RNAs. We show that activating the Neurogenin pathway in ferret progenitors promotes delamination and outward migration. Finally, single-cell transcriptional profiling in human, ferret, and mouse revealed more cells co-expressing proneural Neurogenin targets in human compared to other species, suggesting greater neuronal lineage commitment and differentiation of self-renewing progenitors. Thus, we find that the abundance of human ORG is paralleled by increased transcriptional heterogeneity of cortical progenitors.