Researchers have identified the full suite of 10 factors that regulate the development of brain cell types in fruit flies’ visual system — including the order in which those neurons develop. The results, published in natureopen new avenues of research to understand how brain development evolved in different animals and provide clues for regenerative medicine.
The human brain consists of 80 billion neurons. These nerve cells vary in shape, function, and connectivity with other neurons to form neural networks. This complexity allows the brain to perform its many functions, from controlling language and vision to storing memories and generating emotions.
While scientists have identified many types of neurons, how this complexity arises during brain development is a central question for developmental neurobiology and regenerative medicine.
“Knowing how the human brain develops could, in the future, allow us to replicate these developmental processes in the laboratory to generate certain types of neurons in a petri dish – and possibly transplant them into patients – or trigger neural stem cells in living organisms.” to create and replace missing neurons,” said Claude Desplan, Silver Professor of Biology at NYU and senior author of the study.
Because studying the human brain is an incredibly complex endeavor, researchers rely on model organisms such as mice and flies to explore the intricate mechanisms involved in brain processes. In both vertebrates, such as mice and humans, and invertebrates, such as flies, different types of neurons are generated sequentially as the brain develops, with certain types of neurons being generated first and other types later from the same progenitor stem cell.
The mechanism by which neural stem cells produce different neurons over time is called temporal pattern. Neural stem cells produce different neurons by expressing different molecules – called temporal transcription factors or tTFs – that regulate the expression of specific genes in each time window.
In the study published in naturethe researchers examined the brain of the fruit fly Drosophila to uncover the full set of tTFs needed to generate the roughly 120 neuron types of the medulla, a specific brain structure in the visual system of flies. They used cutting-edge single-cell mRNA sequencing to obtain the transcriptome — all of the genes expressed in a given cell — from more than 50,000 individual cells, which were then grouped into most of the cell types present in the developing spinal cord.
Focusing on neural stem cells, the researchers identified the full set of tTFs that define the different time windows in this brain region, as well as the genetic network that controls the expression of these different tTFs that allow this temporal cascade to progress.
“Several tTFs have previously been identified in the brain’s visual system using available antibodies; we have now identified the comprehensive series of 10 tTFs that can specify all neuron types in this brain region,” said one of the study’s lead authors, Nikolaos Konstantinides, now a group leader at the institute Jacques Monod in Paris and former postdoctoral fellow in the Desplan laboratory.
The researchers then identified the genetic interactions that allow the temporal cascade to progress, and how that progress relates to the ‘birth order’ of all neurons in the spinal cord, by linking specific temporal windows to the generation of specific types of neurons. This cascade is necessary to generate the full extent of the neuronal diversity of this brain region in a stereotyped order.
“Impairing the temporal cascade progression leads to the generation of decreased neuronal diversity and thus altered brain development,” said Isabel Holguera, a postdoctoral researcher in NYU’s Department of Biology and one of the study’s co-first authors.
Finally, the team studied the first steps in the process of neural stem cell maturation into neurons, a stage in neuron development called differentiation. They found that the differentiation process for fly neurons and human cortical neurons was remarkably similar, with similar patterns of genes expressed during different stages of differentiation.
“Our results suggest that understanding the mechanisms of neuron development in flies can provide insights into the equivalent process in humans,” said co-first author Anthony Rossi, now a Harvard postdoctoral fellow and former graduate student in the Desplan lab.
Other study authors include NYU’s Aristides Escobar, Liébaut Dudrane, Yen-Chung Chen, Thinh Tran, Azalia Martinez Jaimes, Mehmet Neset Özel, and Félix Simon; Zhiping Shao, Nadejda M. Tsankova, John F. Fullard and Panos Roussos from the Icahn School of Medicine at Mount Sinai; and Uwe Walldorf from Saarland University. The research was supported by the National Institutes of Health (EY019716, EY10312, K99 EY029356-01, T32 HD007520), NYU, the Human Frontier Science Program, and the Leon Levy Foundation.