FRIPRO-Fri prosjektstøtte

In this project, we are trying to understand better how animals generate nerve cells. The behaviour of almost all animals is controlled by nervous systems. In order to form a functional nervous system, animals have to generate the right number and the right types of nerve cells. This occurs mainly early in life, during embryonic development, but there is also a continuous need to add or replace nerve cells in adult organisms. While the ability to generate nerve cells as embryos is shared by all animals, the capacity to generate them as adults differs considerably between animal groups. Our brain, for example, consists of a vast number of nerve cells, but these are almost exclusively generated when we are embryos, whereas our ability to generate nerve cells as adults is very limited. In this project, we are studying an animal that can generate nerve cells both as an embryo and as an adult, the starlet sea anemone Nematostella vectensis. This animal has a rather simple nervous system without a brain, which likely reflects an early stage during evolution. However, it can generate nerve cells throughout its entire body and it can easily regenerate its nervous system after it has been damaged. Importantly, some of the key genes that control the generation of nerve cells are the same in Nematostella and in humans. There must, however, also be differences that explain why these animals can generate nerve cells so much better than we do. We are employing a broad range of molecular biology methods to understand how different aspects of the activity and the organization of the genome may change when embryos become adults and how this affects the ability to generate nerve cells. From this we hope to learn more about the core principles that guide the generation of nerve cells in animals and which factors might control the ability of an animal to produce them also as adults. In 2023, we focused on two aspects of this project. The first one is the ability of our model organism Nematostella to generate nerve cells in the gastric cavity, which can be compared to our intestine. Mammals like mice or humans also have plenty of nerve cells in the intestine, but these nerve cells are generated in other tissues that are specialized for their production and then migrate into the intestine. The sea anemone, in contrast, produces the nerve cells in this intestinal tissue, a capability that is hardly ever found in other animals. We now completed our work on the function of a gene that is specifically required for the formation of the nerve cells in the gastric cavity, but not for those in other tissues. We were able to show that this gene is active in cells that divide (i.e. a type of stem cell) and then give rise to nerve cells that most likely are involved in regulating the musculature of these animals. These findings were published in the journal Nature Communications (https://www.nature.com/articles/s41467-023-39789-4). The other aspect that we focused on is the unexpected observation that removal of the nervous system from adult animals interferes with their ability to regenerate the correct body parts after bisection. Normally, bisected animals will regenerate a new head from the remaining foot piece, and a foot from the remaining head piece. After removal of the nervous system, both pieces regenerate a new head, i.e. the head piece forms a body with two heads. We characterized the molecular changes that might result in this defect and found that after nervous system removal, genes that are normally only active in the head end are now active throughout the animal. In normal animals, the nervous system thus appears to be required for suppressing a head regeneration program. We are now preparing a publication of these findings.

The training provided during the project in combination with the scientific output improved the career perspectives of the doctoral and postdoctoral participants, e.g. for securing an ERC starting grant and a tenured position in academia. For the PI, the scientific output improved the competitiveness for national and international funding. The project fostered collaborations with research groups in Spain, France and Israel, and these collaborations will continue to lift the international visibility of NFR funded research.

Neurogenesis is a fundamental embryonic process that is essential for the formation of functional neural circuitry and impairment of this process is detrimental for brain function. Moreover, reactivation of neurogenesis in adult nervous systems is an important aspect of the mitigation of neuropathological conditions. During embryogenesis, vertebrates generate neurons from a restricted area of the ectoderm and their capacity to generate neurons as adults is low, which limits their ability to recover from loss or damage of neural tissue. This project utilizes the unique biology and technical amenability of a new model system to provide new insight into the factors that control the ability to generate neurons. The sea anemone Nematostella vectensis produces neurons throughout its body column during embryogenesis and we have established a new transgenic model to show that it can repeatedly regenerate its entire nervous system after conditional ablation. As in vertebrates, embryonic neurogenesis in Nematostella is controlled by Notch, soxB and proneural bHLH genes. Thus, the unrestricted neurogenic potential of these animals is mediated by conserved signalling molecules and transcription factors, but the mechanisms that activate this neurogenic program must be divergent to allow the widespread occurrence of neurogenesis. Here, we use four transgenic reporter lines that identify specific neural cell types to decipher the gene regulatory network and the epigenetic landscape of neural progenitor cells and differentiated neurons. We determine the transcriptional program that governs the regeneration of the nervous system and we use functional analyses to identify key regulators of the neurogenic networks that control embryonic and regenerative neurogenesis. This approach directly provides fundamental insights into the principles of neurogenesis and will serve as an important reference point for studies that aim at overcoming the limited neurogenic potential of vertebrates