The human brain is known to contain a wide range of cell types, which have different roles and functions. The processes via which cells in the brain, particularly its outermost layer (i.e., the cerebral cortex), gradually become specialised and take on specific roles have been the focus of many past neuroscience studies.

Researchers at the University of California Los Angeles (UCLA) analysed different datasets collected using single-cell transcriptomics, a technique to study gene expression in individual cells, to map the emergence of different cell types during the brain's development.

Their findings, published in Nature Neuroscience, unveil gene "programs" that drive the specialisation of cells in the human cerebral cortex.

"This project initially began as a small bioinformatic side project," Aparna Bhaduri, senior author of the paper, told Medical Xpress.

"We were integrating publicly available datasets to explore gene expression patterns during brain development, but as we progressed, we realised that these gene networks—or modules—provided valuable insights into how distinct cell types emerge in the developing human cortex. Recognising the potential impact of these findings, we expanded the work into a comprehensive study."

The primary objective of the study by Bhaduri and her colleagues was to uncover co-expression gene networks that contribute to the specification of cell types in the cerebral cortex. Uncovering these genetic modules could in turn shed new light on the overall processes underpinning the healthy and atypical development of the human brain.

"Over the past few years, many different research groups have made molecular profiles of the developing human brain," Patricia R. Nano, first author of the paper, told Medical Xpress. "Given the complexity of the brain, however, each of these profiles understandably covers only certain timepoints of brain development."

The team's study began as a small side project aimed at better understanding large datasets collected over the past decades and integrating them into a "meta-atlas" of gene expression at the single-cell level. After they had created this meta-atlas, however, Bhaduri, Nano and their colleagues realised that they could use it to identify gene modules driving cell specialisation.

"Once we saw that these modules could represent how different cell types are formed and refined, we knew we had something that could really help others examining the developing human brain," said Nano. "Our work then expanded into a paper that set out to not only identify the modules that shape the human brain, but also to test the functions of these modules in models of human brain development."

As a first step in their study, the researchers combined and collectively analysed data collected in previous research that employed single-cell RNA sequencing techniques. These data essentially describe the gene activity in individual cells during the brain's development.

"By clustering genes that showed similar expression patterns across these diverse datasets, we identified 'gene co-expression networks' or modules, representing groups of genes working together during specific developmental stages," explained Bhaduri.

"To validate our findings, we tested whether these modules were active in actual human brain tissues, confirming their expression patterns using microscopy and staining methods."

After they confirmed that identified gene modules were active in actual human brain tissues, the researchers conducted further experiments using brain organoid models, which are three-dimensional (3D) and miniaturised models of the developing human brain created using stem cells. Using these models, they experimentally verified that these modules contributed to the formation of specific neuron types.

"Our study identified and validated specific gene networks that drive the development of distinct neuron subtypes in the human cerebral cortex," said Bhaduri. "For instance, we characterised modules essential for creating deep-layer neurons, revealing previously unknown roles for genes associated with neurodevelopmental disorders."

The study gathered new, valuable insight into the genetic processes underpinning the emergence of the human cerebral cortex's complexity during the early stages of development.

In the future, the meta-atlas created by the researchers could also help to better understand the precise genetic and molecular mechanisms behind the development of various developmental disorders, including autism and intellectual disabilities.

"What people have told us to be particularly helpful is the fact that, from datasets made by different labs at different times, we were able to identify gene modules that describe how cell fates arise—providing ways to take maps of the human brain and extract the mechanisms by which it forms," said Nano.

"Similarly to the example Aparna mentioned, our modules can reveal new ways by which disease-risk genes can control specific cell types in the brain."

Bhaduri, Nano and her colleagues hope that the meta-atlas they created will be a valuable resource for other research groups worldwide. For instance, it could help neuroscientists to pinpoint gene networks that are disrupted in individuals diagnosed with specific developmental and neurological disorders, which could in turn be targeted by new therapeutic interventions.

"We are very excited to continue to understand how the human brain comes to be and how these gene programs are important in healthy development and neurological disorders," added Bhaduri.

"For example, we have used a similar meta-atlas approach in glioblastoma, a deadly brain cancer, and are integrating our meta-atlas of human brain development with other measures of stem cell function and decision making.

"We are also interested in further exploring additional neurodevelopmental disorders and comparing modules from this developmental atlas to those developmental trajectories."

--Ingrid Fadelli