Interactions of signalling pathways in genome maintenance during neurogenesis

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The aim of this project is to understand how chromosomal instability arises in the developing brain. Neural progenitors and neurons are hotspots for mosaicism, which has been associated with neuronal specialization, as well as several neuro-developmental disorders and aging diseases. However, how genome stability is monitored across different developmental lineages - including in the brain - remains largely uncharacterized. In proposal specific results, we identified that the brain patterning signals Wnt and FGF form a tug-of-war that regulates chromosome segregation fidelity during neurogenesis. Here, we will employ human and mouse neural stem cell models to characterize the functional interactions between FGF and Wnt signalling pathways, and to determine their contribution to the notoriously high levels of genomic mosaicism in the brain. First, we will characterize the contribution of FGF and Wnt to structural and numerical chromosome maintenance during in vitro human neuronal specification, including by state-of-the-art single cell genome and transcriptome sequencing. Second, we will define the spatio-temporal roles of this novel signalling tug-of-war in the control of chromosome stability in neural progenitors and neurons during in vivo mouse brain development. The discovery of a moonlighting role of patterning signals as sources of chromosome (in)stability constitutes a ground-breaking new principle in development. Our work will provide novel insights relevant to prevent genomic abnormalities in stem cells that currently preclude their therapeutic application, and to understand why genomic mosaicism is prevalent in the brain, but no in other organs. Finally, our work could open new avenues to investigate neuro-developmental disorders associated with chromosomal instability.