Researchers have mapped the development of the human neocortex, analyzing gene activation and cellular organization from gestation to adolescence. They identified a new type of progenitor cell (Tri-IPC) that can generate different cell types and has similarities to brain cancer cells. The study also linked genes linked to autism to neurons formed in the second trimester of pregnancy, offering new insights into neurological disorders and brain development.
The development of the human neocortex, the part of the brain responsible for functions such as thought, memory and sensory perception, is a highly complex and coordinated process.
During this phase, cells called radial glia act as “factories” that generate excitatory neurons, which send electrical signals in the brain. These neurons are produced in a specific sequence and then migrate to their final positions in the neocortex, where they form organized layers and connections essential for brain function.
At the same time, another type of neuron, inhibitory neurons, which help balance brain activity, move from another region of the brain to the cortex, where they integrate into the neural network.
At the end of the second trimester of pregnancy, the brain enters a new phase: instead of producing only neurons, progenitor cells begin to generate astrocytes and oligodendrocytes, cells that support and protect neurons.
Graphical summary of cell lineage relationships in the human neocortex at the end of the second trimester.
This entire process is controlled by complex genetic mechanisms that determine which genes are turned on or off at each stage of development. Despite scientific advances, there are still many gaps in our understanding of how these mechanisms work.
In recent years, new technologies have made it possible to study the cellular diversity and molecular processes of brain development in greater detail. However, many of these studies have analyzed active genes and changes in DNA structure separately, without integrating this information.
Researchers at the University of California, San Francisco conducted an in-depth study to fill this gap. They collected and analyzed samples of the human neocortex at different ages, from the first trimester of pregnancy through adolescence, to better understand how brain cells form and organize themselves.
The team used advanced techniques to map which genes were active in each cell and which regions of DNA were accessible for gene regulation. They also performed spatial analysis to understand how cells communicate with each other and organize themselves within the brain.
This resulted in the creation of a detailed “atlas” of the development of the neocortex, allowing them to identify cellular patterns and trajectories over time.
Cell-to-cell communication in the developing human neocortex. Spatial transcriptomic analysis of six neocortical samples. Cells are color-coded by type or niche to which they belong.
One of the most important findings of the study was the identification of a new type of progenitor cell called Tri-IPC. This cell has the ability to generate three different types of cells: inhibitory neurons, astrocytes, and oligodendrocyte precursor cells.
In addition, the researchers noted that glioblastoma cells, an aggressive type of brain cancer, behave similarly to Tri-IPCs.
This suggests that cancer may be "hijacking" natural developmental processes to grow and become more diverse.
Another important finding was the relationship between genes linked to autism and intratelencephalic neurons formed in the second trimester of pregnancy.
By combining their data with genetic studies on disease risk, the researchers created a map that could help us better understand how certain neuropsychiatric conditions, such as autism spectrum disorder, may be related to brain development.
This study provides a more detailed look at the cellular and genetic processes involved in the formation of the human neocortex, contributing to the advancement of knowledge about neurological disorders and even brain cancer.
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Molecular and cellular dynamics of the developing human neocortex
Li Wang, Cheng Wang, Juan A. Moriano, Songcang Chen, Guolong Zuo, Arantxa Cebrián-Silla, Shaobo Zhang, Tanzila Mukhtar, Shaohui Wang, Mengyi Song, Lilian Gomes de Oliveira, Qiuli Bi, Jonathan J. Augustin, Xinxin Ge, Mercedes F. Paredes, Eric J. Huang, Arturo Alvarez-Buylla, Xin Duan, Jingjing Li and Arnold R. Kriegstein
Nature (2025). 08 January 2025
Abstract:
The development of the human neocortex is highly dynamic, involving complex cellular trajectories controlled by gene regulation1. Here we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 human neocortical samples encompassing both the prefrontal cortex and the primary visual cortex. These samples span five main developmental stages, ranging from the first trimester to adolescence. In parallel, we performed spatial transcriptomic analysis on a subset of the samples to illustrate spatial organization and intercellular communication. This atlas enables us to catalogue cell-type-specific, age-specific and area-specific gene regulatory networks underlying neural differentiation. Moreover, combining single-cell profiling, progenitor purification and lineage-tracing experiments, we have untangled the complex lineage relationships among progenitor subtypes during the neurogenesis-to-gliogenesis transition. We identified a tripotential intermediate progenitor subtype—tripotential intermediate progenitor cells (Tri-IPCs)—that is responsible for the local production of GABAergic neurons, oligodendrocyte precursor cells and astrocytes. Notably, most glioblastoma cells resemble Tri-IPCs at the transcriptomic level, suggesting that cancer cells hijack developmental processes to enhance growth and heterogeneity. Furthermore, by integrating our atlas data with large-scale genome-wide association study data, we created a disease-risk map highlighting enriched risk associated with autism spectrum disorder in second-trimester intratelencephalic neurons. Our study sheds light on the molecular and cellular dynamics of the developing human neocortex.
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