New frontiers in understanding brain development

This webinar will cover how these atlases provide developmental timelines and comparative frameworks, benchmarking cell types and anatomy across mammalian species, and in organoids, to understand how genes and regulatory programs shape region-specific cell types, define progenitor diversity and developmental “switches” in neurogenesis, reveal sex-specific developmental programs, uncover evolutionary changes that define primate-specific cell types and brain features, and begin to identify particular cell type vulnerabilities. We will also showcase new Open Science resources that emerge from the latest scientific research on brain development, with open-access, large-scale data and new multi-modal tools to map the developing mammalian brain.

There will be time for Q&A with the presenters at the end of the presentations.

Research presented in this webinar has been supported by the BRAIN Initiative Cell Census Network (BICCN) and BRAIN Initiative Cell Atlas Network (BICAN) of the National Institutes of Health.

Speakers in order:

Hongkui Zeng, PhD, Allen Institute

Overview

Carlo Colantuoni, PhD, Johns Hopkins & Univ. of Maryland

NeMO Analytics: A Curated Compendium of Transcriptomic Data for the Exploration of Neocortical Development

At NeMO Analytics we have assembled a vast collection of public transcriptomic data to fuel the global exploration of neocortical development: https://nemoanalytics.org/landing/neocortex. Applying our joint matrix decomposition methods to many datasets from this collection, we define elements of transcriptome dynamics that are conserved across the mammalian lineage and others that are specific to human development. Additionally, we define layer-specific transcriptomic signatures of adult human neocortical neurons and chart their protracted emergence in development and their notable absences from most organoid models

Aparna Bhaduri, PhD, UCLA

Integrated analysis of molecular atlases unveils modules driving developmental cell subtype specification in the human cortex

Human brain development requires generating diverse cell types, a process explored by single-cell transcriptomics. Through parallel meta-analyses of the human cortex in development (seven datasets) and adulthood (16 datasets), we generated over 500 gene co-expression networks that can describe mechanisms of cortical development, centering on peak stages of neurogenesis. These meta-modules show dynamic cell subtype specificities throughout cortical development, with several developmental meta-modules displaying spatiotemporal expression patterns that allude to potential roles in cell fate specification. We validated the expression of these modules in primary human cortical tissues. These include meta-module 20, a module elevated in FEZF2+ deep layer neurons that includes TSHZ3, a transcription factor associated with neurodevelopmental disorders. Human cortical chimeroid experiments validated that both FEZF2 and TSHZ3 are required to drive module 20 activity and deep layer neuron specification but through distinct modalities. These studies demonstrate how meta-atlases can engender further mechanistic analyses of cortical fate specification.

Di Zhang, PhD, Yale

Spatial dynamics of brain development and neuroinflammationThe ability to spatially map multiple layers of omics information across developmental time points enables exploration of the mechanisms driving brain development1, differentiation, arealization, and disease-related alterations. Here, we applied spatial tri-omic sequencing, including spatial ARP-seq (spatial ATAC–RNA–Protein-seq) and spatial CTRP-seq (spatial CUT&Tag–RNA–Protein-seq), alongside multiplexed immunofluorescence imaging (CODEX) to map dynamic spatial remodeling during brain development and neuroinflammation. We generated a spatiotemporal tri-omic atlas of the mouse brain from postnatal day 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 uncovered a role for layer-specific projection neurons in coordinating axonogenesis and myelination. In a lysolecithin (LPC) 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 work reveals common and differential mechanisms underlying brain development and neuroinflammation, providing a rich resource for investigating brain development, function, and disease.

Yongsoo Kim, PhD, Penn State University

Developmental mouse brain common coordinate framework

We have created a detailed 3D map showing how the mouse brain develops from early embryo to adulthood. This new resource helps researchers study brain growth and explore cell changes, and it’s freely available online for anyone to use. By making data from different studies easier to compare, it supports new discoveries in how brains form and function.

Yuan Gao, PhD, Allen Institute

Continuous cell type diversification in mouse visual cortex development

Using single-cell transcriptomic and epigenomic profiling we created a high temporal resolution atlas of cell types in the developing mouse visual cortex. Prior studies in the adult brain have identified approximately one hundred distinct cell types. We computationally reconstructed developmental trajectories of glutamatergic and GABAergic neuron types, as well as glia, providing an incredibly detailed molecular map of Ph.D., changes throughout development of the visual cortex. The current work revealed that cell type diversification is remarkably continuous, with more refined neuron types emerging at different postnatal stages. This process coincides with various circuit maturation events, and the results further linked this diversification with cell-type specific and temporally resolved gene regulatory networks.

Cindy van Velthoven, PhD, Allen Institute

Transcriptomic and spatial organization of telencephalic GABAergic neurons

GABAergic neurons play critical roles in neural computations. Their dysfunction is a hallmark of major neurological and psychiatric disorders. We conducted a comprehensive analysis of the transcriptomic diversity of GABAergic neurons and their spatiotemporal distribution in the mouse telencephalon. These analyses revealed exceptional complexity within and across brain regions, revealing unexpected and striking patterns of long-range migration of nearly all classes of GABAergic neurons. The study found that individual types of GABAergic neurons follow a cell type-specific tempo of maturation. Cortical and striatal GABAergic neurons undergo extensive postnatal diversification, whereas septal, preoptic and most pallidal GABAergic neuronal types emerge simultaneously during the embryonic stage with limited postnatal diversification.

Emily Corrigan, UCSF

Conservation and alteration of mammalian striatal interneurons

We survey gene expression from 10 mammalian species, spanning 160 million years of divergence, and discover that TAC3 interneurons, previously thought to be a primate specific population, instead represent a conserved, ancestral population with modified gene expression and distribution throughout evolution. This finding suggests that brain evolution among mammals occurs through fate refinement of initial classes during development, rather than the generation of entirely novel populations.

Marilyn Steyert, UCSF

Lineage-resolved atlas of the developing human cortex

We applied prospective lineage tracing to map the manifold of human neural stem and progenitor cell differentiation across the developmental window encompassing neurogenesis and gliogenesis in human primary tissue. We show that some cortical progenitors switch from glutamatergic to GABAergic neurogenesis around midgestation, which coincides with an onset of oligodendrocyte generation. Unexpectedly, we find that truncated radial glia generate late-born glutamatergic neurons which exhibit molecular features of deep cortical layer neurons, and may contribute to the expansion of the subplate region during midgestation.

Harris Kaplan, PhD, Harvard University

A coming-of-age story: developmental changes in neurons regulating social and homeostatic functions

Animal behavior changes considerably over postnatal development. Early in life, homeostatic needs like hunger or thermoregulation are met through social interactions; upon weaning and puberty, animals become physiologically independent, and sex-specific social behaviors mature. To understand how these changes relate to changes in the brain, we examined gene expression changes across birth, weaning and puberty in the mouse hypothalamus, a brain region that contains specific circuits controlling different homeostatic and social functions.

Camiel Mannens, PhD, Karolinska Institute, Flemish Institute for Biotechnology (VIB)

Chromatin accessibility during human first-trimester neurodevelopment

The lineage relationships between individual human cortical progenitors and the diverse cell types they produce remains largely unknown. We applied prospective lineage tracing to map the manifold of differentiation across neurogenesis and gliogenesis. We show that some cortical progenitors switch from glutamatergic to GABAergic neurogenesis around midgestation, which coincides with an onset of oligodendrocyte generation. Unexpectedly, we find that truncated radial glia generate late-born glutamatergic neurons which exhibit molecular features of deep cortical layer neurons, and may contribute to the expansion of the subplate region during midgestation.

Li Wang, Stanford University

Molecular and cellular dynamics of the developing human neocortex

We generated a comprehensive multi-omic and spatial atlas of the developing human neocortex, profiling chromatin accessibility and gene expression across key prenatal stages and cortical regions. We identified a tripotential intermediate progenitor cell (Tri-IPC) capable of generating interneurons, oligodendrocyte precursors, and astrocytes, a developmental state notably reactivated in glioblastoma. Integration with GWAS data further linked specific neuropsychiatric and cognitive traits to distinct cell types and developmental windows, connecting normal brain development to disease risk.