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 2022, we continued our work on the role of so-called chromatin-modifying proteins, which are enzymes that modify the genetic material to control which genes can be activated and which ones are silent in different cells. These enzymes often form complexes in which several of them are assembled to allow the addition or removal of different modifications in a co-ordinated manner. These complexes are often kept together by specific proteins, which are called scaffolding proteins. They do not themselves modify the chromatin, but they bind to several of the modifying enzymes to form larger complexes. In our work published in 2022, we show that one of these scaffolding proteins acts specifically in animals (but not in single-celled organisms) to assemble such a complex of chromatin-modifying enzymes. Based on these observations we hypothesise that the evolution of such scaffolding proteins may have contributed to the emergence of the sophisticated genetic programs that are used by animals to produce their many different cell types. New ways to coordinate the activity of already existing enzymes might thus be an important part of animal evolution. We also analysed in more detail the fascinating ability of our study organisms to rebuild their nervous system after it has been removed. We systematically identified genes that are activated during this process and we are now using this information to study the function of these genes during the regeneration of the nervous system. One of the most surprising observations in this part of the project is that after removal of the nervous system, the animals lose their ability to distinguish the two ends of their body, head and foot. When cut into two halves (one half missing the head, the other one missing the foot), the animals regrow the missing head or foot at the correct site. In the absence of the nervous system, they cannot do this correctly anymore. This suggests that the nervous system informs the other tissues about the part of the body that needs to be regrown. In the final year of the project, we will aim at understanding the molecular basis for this observation.

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