Regulation of Neuronal Differentiation by Micropeptides

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Understanding how tissues grow and develop is a central question in developmental biology. The nervous system is one of the most complex tissues in most animals, and contains some of the most highly specialised cell types. As with all adult tissues, the specialised cells of the nervous system are derived from a set of stem cells which can be found in developing embryos, as well as in later developmental stages, including the adult brain in humans. These neural stem cells divide in a precisely controlled manner to produce neurons, which are the functional cells of the nervous system. Much research has been done to identify genes which are activated in neurons, which in turn regulate further genes that are necessary for neuronal function. Previously, we identified a gene, lola, which acts in the opposite manner - i.e. it maintains cell's neuronal identity by switching off stem cell genes. Animals that are mutants for lola develop brain tumours which are the result of neurons reverting back to stem cells. In an effort to understand how lola mediates these effects, we looked for further genes that interact with lola. Using this approach, we identified an interesting gene, copacobana (copa), which we believe is involved in the regulation of Lola function. In contrast to most genes, which contain the instructions required for the cell to make a large protein product, copa is divided in to a series of smaller functional units called open reading frames (smORFs), which allows this gene to make multiple small peptides. Similar small peptides have been found previously to be involved in various biological processes, however, copa is the first example of its kind to be observed in the nervous system. To understand exactly how copa is functioning in the development of neurons, we are intending to use genetic techniques to create mutant fruit flies in which copa is removed. By observing the development of the nervous system in these mutants, we will be able to determine the action of copa and its relationship to lola. The presence of smORFs within a gene is very difficult to predict. We intend to use recently developed molecular biology techniques to fully characterise the functional regions of copa, which will allow us to more fully appreciate its role in brain development.In depth knowledge of how brain tissues are built is vital for understanding what can go wrong in congenital conditions such as microcephaly, as well as degenerative diseases such as Alzheimer's. In certain cancers, it is thought that cells undergo a reversion to a stem cell like state as observed with our lola mutants. Therefore, this project may help us to understand how that process is able to occur. We hope that this project may help to inform the development of therapeutics for these conditions and others. Furthermore, there is potential for small peptides such as the ones made by copa to be used for pharmacological or industrial purposes. smORF-containing genes are very difficult to identify, and there are currently only a handful of validated examples of this phenomenon. By identifying and characterising functional peptides which are active in the brain we are advancing our understanding of a fascinating nascent biological field. Identifying proof-of-principle of smORF action has the potential to impact almost all areas of bioscience.