Brain_stability · Elucidating novel post-transcriptional regulatory mechanisms in neural development

Elucidating novel post-transcriptional regulatory mechanisms in neural development

The development of the brain is one of the most complex examples of tissue building in the animal world. During brain development, a small population of neural stem cells gives rise to a plethora of specialized cell types, each linked to its neighbours by an intricate web of connections. It is not understood how these cell types are produced at the appropriate time in development and how each progenitor cell chooses its fate at the precise place and time. Most studies on this topic have focused on identifying specific master regulators, known as transcription factors, that are required to specify particular cell lineages. However, in many cases it is not known what regulates the transcription factors themselves. How are they activated in the correct cell types, and how is their activity repressed in other cell types? We hypothesized that different levels of gene regulation, some of them occurring post-transcriptionally and outside the direct purview of transcription factors, could provide the more fine-grained control of development that is needed in this context. The main objective of this project was to determine whether post-transcriptional regulation, at the level of RNA stability, contributes to developmental decisions during brain development. This objective was split into several sub-objectives. Firstly, we aimed to measure RNA stability during brain development using the fruit fly larval brain as a model. Secondly, we sought to identify potential regulators of RNA stability using this dataset. Finally, we aimed to discover the functional relevance of RNA stability regulation for brain development using the power of fly genetics and the sophisticated assays we have at our disposal, including live explant brain culture. The brain is the most complicated human organ, but it is also the most quintessentially human. As a species, our drive to learn more about the brain stems from deep existential questions and not scientific fervour alone. The more we learn about the brain, the closer we are to understanding our inner thoughts and how we interact with each other. These findings have potential to influence every sphere of society, including education, law, and politics. Understanding the development, or initial wiring of the system, is the foundation of brain science and greatly complements the work of neuroscientists who focus on the functioning of the adult brain. Even apart from its value in the broader context of advancing neuroscience, studying brain development has key societal implications. The proliferation of neural cells is precisely regulated during brain development and misregulation of these molecular pathways can lead to childhood diseases in humans, such as brain tumours or developmental delay. We have identified and are characterizing molecular pathways that we believe to be important for limiting the proliferation potential of neural stem cells and other pathways that we believe to be important for specifying the birth of a particular cell type. In the future, the results of our studies may help pharmaceutical companies select drug targets for the treatment of these disorders.

Data: CORDIS, © European Union