The cerebral cortex is densely packed with different nerve cells that enable us to perceive, think and act. Yet how these cell types arise while the brain develops is still not fully understood. Irene Varela-Martínez, a postdoctoral researcher at the Institute of Science and Technology Austria (ISTA), traces their origins like a family-tree detective of nerve cells. Her new study, now published in Science Advances, shows that precursor cells of neurons, contrary to previous assumptions, split early into two independent lineages and thereby give rise to types of neurons.
Science thrives on exchange. Whether at conferences, symposia, Zoom calls, or visits to other research institutes and universities—Irene Varela-Martínez can tell you a thing or two about it.
In her PhD project at the Centro Nacional de Biotecnología (CNB-CSIC) in Madrid, in the lab of Marta Nieto , the neuroscientist investigated how precursor cells—stem cells—in the cerebral cortex develop and how they form different groups of nerve cells. During the data collection, she also spent time (supported by an EMBO short-term fellowship) at the Institute of Science and Technology Austria (ISTA) in Simon Hippenmeyer's group . A time she looks back on fondly—and one she is now building on as a postdoctoral researcher at ISTA.
The results of this work have now been published in Science Advances and show that precursor cells, different than previously thought, split very early into two lineages and thereby give rise to distinct types of neurons.
Part of the gray matter
"It's time to get the gray matter going" or "a bit of input for the gray matter": there are many sayings about putting the brain to work. A large part of this gray matter is formed by the cerebral cortex—the outermost layer of our brain. There, neurons and glial cells sit densely packed, playing an enormous role in attention, perception, consciousness, thinking, memory, and language.
In the cerebral cortex, projection neurons—nerve cells that "project," or send, signals over longer distances into brain regions or the nervous system—can be broadly divided into two groups. These include the intra-telencephalic projection neurons—IT-PNs for short—which establish connections to other areas of the cerebral cortex, including the opposite brain hemisphere. Another group is the extra-telencephalic projection neurons, ET-PNs for short. They send their processes out of the cerebral cortex, for example toward the spinal cord.
All of these neurons are born during neurogenesis—the developmental phase of nerve cells. Until now, however, it remained unclear how neural stem cells 'decide' which type of projection neuron to produce.
"The cerebral cortex consists of six layers," explains Varela-Martínez. "During brain development, these layers are gradually populated with neurons. According to the 'inside-out' model, cortical nerve cells for the deeper layers arise first, followed by neurons that settle in progressively more superficial layers." This led researchers to assume that neural stem cells first generated ET-PNs, which only populate the deep layers, and only later switched to producing IT-PNs, which are enriched in the upper layers.
However, it does not seem to be that simple. The first results from Varela-Martínez and her colleagues showed that, in mice, rather than following a strict temporal switch from one neuronal subtype to another, the production of ET-PNs and IT-PNs partially overlaps. Perhaps more importantly, each subtype follows its own distinct neurogenic dynamics.
Neuronal branches
With these results in hand, the then-PhD student came to the Hippenmeyer group as a visiting scientist.
"The group has great expertise in the gold-standard MADM technique. This method allows you to precisely follow cell division during the development of neurons," explains Varela-Martínez. "With it, daughter cells can be made visible—and beyond that, the entire cell lineages and cell clones can be reconstructed."
Using this technique, Varela-Martínez set out to search for how the two cell types, ET-PNs and IT-PNs, differ in their lineages. So-called radial glial cells were the starting point—neuronal precursor cells from which the projection neurons of the cerebral cortex arise.
This lineage analysis showed that there are at least two developmental branches that originate in parallel from this precursor cell and separate from each other already early on. One branch gives rise exclusively to IT-PNs, while the other produces both ET-PNs and IT-PNs. This finding refines the long-standing view that radial glial progenitors follow a single developmental program, producing ET-PNs first and IT-PNs later.
Importantly, the production of the two neuronal groups does not follow the same developmental dynamics. While ET-PNs are generated in small clusters that become exhausted early, IT-PN lineages consist of larger groups of neurons, distributed across all cortical layers. This explains why ET-PNs predominate early in development, whereas later neurogenesis produces almost exclusively IT-PNs.
Overall, the study suggests that the cerebral cortex is built through an early branching process, in which different neuronal lineages arise in parallel from the very beginning.
New project at ISTA
For almost a year now, Varela-Martínez has been a postdoc at ISTA. Although the researcher is still dedicated to the cerebral cortex, the question is now a different one. The neuroscientist is trying to understand how the size and complexity of the cerebral cortex have changed over the course of evolution.
To do so, she investigates how the developmental programs of neural stem cells have evolved to generate larger numbers of neurons.
"Across evolution, brains have become larger and more complex," explains Varela-Martínez. "How have neural stem cells adapted to generate more and even more diverse neurons? How is this achieved at the lineage level?"
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Information on animal studies
In order to better understand fundamental processes, for example, in the fields of neuroscience, immunology, or genetics, the use of animals in research is indispensable. No other methods, such as in silico models, can serve as an alternative. The animals are raised, kept, and treated according to the strict regulations of Austrian law. All animal procedures are approved by the Federal Ministry of Women, Science, and Research.
