Adapted from "Scientists complete first drafts of developing mammalian brain cell atlases," by Liz Dueweke, Allen Institute
A global consortium of scientists has created the first and most detailed “developmental maps” of the mammalian brain (from mouse to human) to date, taking the critical first steps in unraveling the mystery of early brain development and the vital role it plays in health and disease. Life-altering neurodevelopmental disorders that lead to significant cognitive, communicational, behavioral, or psychomotor impairments affect 15% of children or adolescents worldwide, with diagnoses of autism and attention deficit hyperactivity disorders (ADHD) increasing in the United States. In humans, this early phase of brain development is uniquely long, so understanding this critical phase where things can go wrong is essential for illuminating our understanding of and treating brain disorders.
In a package of 12 studies published in the Nature family of journals, researchers reveal new features of mammalian cell types during early development and begins to shed light on the environmental factors — including sensory inputs and social behavior — that affect how brains develop. The resulting comprehensive, cross-species developing brain cell atlases lay the foundation and provide powerful tools for a new era in the understanding of the human brain in health and disease.
“It's really been a long-standing mystery to understand how these processes occur,” said Tomaz Nowakowski, PhD, one of the study authors and associate professor of neurological surgery, anatomy, psychiatry and behavioral sciences at UCSF. “Building on the findings from the adult brain and venturing into the developmental stages is profoundly important because it is going to inform our understanding of the vulnerabilities and mutations which can lead to neurodevelopmental disorders.”
This landmark achievement was supported by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative®, aimed at accelerating the development of innovative neurotechnologies and revolutionizing our understanding of the human brain.
UCSF Broad Stem Cell Center scientists contributed several significant findings:
Molecular and cellular dynamics of the developing human neocortex | Li Wang, Cheng Wang, Juan Moriano, Songcang Chen, Shaobo Zhang, Tanzila Mukhtar, Shaohui Wang, Arantxa Cebrián-Silla, Qiuli Bi, Jonathan Augustin, Lilian Gomes de Oliveira, Mengyi Song, Xinxin Ge, Guolong Zuo, Mercedes Paredes, Eric Huang, Arturo Alvarez-Buylla, Xin Duan, Jingjing Li, and Arnold Kreigstein created a single-cell multi-omic atlas of the developing human neocortex, identifying tripotential intermediate progenitors that generate GABAergic neurons, oligodendrocyte precursors, and astrocytes. This study also revealed transcriptomic similarities between glioblastoma cells and these progenitors, and linked second-trimester intratelencephalic neurons to autism risk.
Lineage-resolved atlas of the developing human cortex | Matthew Keefe, Marilyn Steyert, and Tomasz Nowakowski utilized barcoded lineage tracing to uncover a developmental switch in the human cortex from glutamatergic to GABAergic neurogenesis. They show that cortical progenitors switch from glutamatergic to GABAergic (involving γ-aminobutyric acid) neurogenesis around midgestation, which coincides with an onset of oligodendrocyte generation. Additionally, they find that truncated radial glia maintain a glutamatergic neurogenic potential for a protracted period during human cortical development. Their results suggest that the late second trimester is a critical timepoint for developmental transitions in cortical neurogenesis.
Spatial dynamics of brain development and neuroinflammation | Mengyi Song, Li Wang, Shaohui Wang, Arnold Kriegstein, and colleagues reveal common and differential mechanisms underlying brain development and neuroinflammation, providing a rich resource for investigating brain development, function and disease. The team 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.
Conservation and alteration of mammalian striatal interneurons | Emily Corrigan, Michael DeBerardine, Aunoy Poddar, Miguel Turrero García, Matthew Schmitz, Corey Harwell, Mercedes Paredes, Fenna Krienen, and Alex Pollen surveyed gene expression across 10 mammalian species and found that TAC3 interneurons, previously thought to be primate-specific, are conserved ancestral populations with altered gene expression and distribution. This work highlights brain evolution through refinement of initial cell classes rather than creation of novel populations.
In addition, Nowakowski, and colleagues authored a perspectives piece, providing a broader context for these findings. Together, these studies reveal the exact timing and patterns by which brain cells grow, specialize, and connect. These discoveries reveal critical windows during development—some even after birth—when the brain is especially sensitive to change. This valuable insight has implications for understanding and treating childhood brain disorders that begin in life’s earliest stages.
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