The human brain is composed of 80 billion neurons that differ in form, function, and how they connect with other neurons to form neural networks. This complexity allows the brain to perform its many tasks, from controlling speech 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.
Now, researchers have identified the complete series of 10 factors that regulate the development of different neuron types in the visual system of fruit flies—including the order in which these neurons develop. The findings, published April 6 in Nature, open new avenues of research to understand how brain development evolved in different animals and may even hold clues for regenerative medicine.
“Our findings suggest that understanding the mechanisms of neuron development in flies can generate insight for the equivalent process in humans,” said co-first author Anthony Rossi, a research fellow in neurobiology at Harvard Medical School, who conducted the research as a graduate student at NYU.
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 the brain’s processes. Vertebrates and invertebrates alike have different types of neurons that are generated sequentially as the brain develops, with specific types being generated first and other types being generated later from the same progenitor stem cell.
The mechanism by which neural stem cells produce different neurons over time is called temporal patterning. Neural stem cells produce different neurons by expressing different molecules—termed temporal transcription factors, or tTFs—that regulate the expression of specific genes in each window of time. This temporal cascade is necessary to produce the full extent of neural diversity in the brain.
“Impairment of the temporal cascade progression leads to the generation of reduced neuronal diversity, hence altering brain development,” said co-first author Isabel Holguera, a postdoctoral fellow in biology at NYU.
In the new paper, the researchers studied the brain of the fruit fly Drosophila to uncover the complete set of tTFs needed to generate the roughly 120 neuron types in the medulla, a brain structure in the visual system. They used state-of-the-art single-cell mRNA sequencing to obtain the transcriptome—all of the genes expressed in a given cell—of more than 50,000 individual cells that were then grouped into most of the cell types present in the developing medulla.
Focusing on neural stem cells, the researchers identified the complete set of tTFs that define the different windows of time in this brain region, along with the genetic network that controls the expression of these different tTFs.
“Several tTFs had been previously identified in the brain’s visual system using available antibodies. We have now identified the comprehensive series of 10 tTFs that can specify all the neuron types in this brain region,” said co-lead author Nikolaos Konstantinides, a group leader at the Institut Jacques Monod in Paris, who conducted the research as a postdoctoral fellow at NYU.
The researchers then pinpointed the genetic interactions that allow the temporal cascade to progress, and determined how this progression relates to the “birth order” of all neurons in the medulla. In doing so, they were able to link specific temporal windows with the generation of specific neuron types.
Finally, the team examined the first steps in differentiation, the process by which neural stem cells mature into neurons. They found that differentiation for fly neurons and human cortical neurons was remarkably alike, with similar patterns of genes expressed during the various stages of the process.
“Knowing how the human brain develops could allow us in the future to repeat these developmental processes in the lab to generate specific types of neurons in a petri dish—and potentially transplant them in patients—or to trigger neuronal stem cells in living organisms to generate and replace missing neurons,” said senior author Claude Desplan, Silver Professor of Biology at New York University.
Funding was provided by the National Institutes of Health (EY019716; EY10312; K99 EY029356-01; T32 HD007520), NYU, the Human Frontier Science Program, and the Leon Levy Foundation.
Additional authors include Aristides Escobar, Liébaut Dudragne, Yen-Chung Chen, Thinh Tran, Azalia Martinez Jaimes, Mehmet Neset Özel, and Félix Simon of NYU; Zhiping Shao, Nadejda Tsankova, John Fullard, and Panos Roussos of the Icahn School of Medicine at Mount Sinai; and Uwe Walldorf of Saarland University.