Interactions of signalling pathways in genome maintenance during neurogenesis

该项目的目的是了解染色体不稳定性如何在发育中的大脑中产生。神经祖细胞和神经元是嵌合现象的研究热点，嵌合现象与神经元的特化以及一些神经发育障碍和衰老疾病有关。然而，如何在不同的发育谱系中监测基因组稳定性-包括在大脑中-仍然在很大程度上没有特征。在具体的结果中，我们发现大脑模式信号Wnt和FGF形成了一场拔河比赛，在神经发生过程中调节染色体分离的保真度。在这里，我们将采用人类和小鼠神经干细胞模型来表征FGF和Wnt信号通路之间的功能性相互作用，并确定它们对大脑中众所周知的高水平基因组嵌合体的贡献。首先，我们将表征FGF和Wnt在体外人类神经元特化过程中对结构和数量染色体维持的贡献，包括通过最先进的单细胞基因组和转录组测序。其次，我们将定义这种新的信号拔河在体内小鼠大脑发育过程中的神经祖细胞和神经元的染色体稳定性控制的时空作用。模式信号作为染色体稳定性来源的兼职作用的发现构成了开发中的突破性新原理。我们的工作将提供新的见解，以防止目前妨碍其治疗应用的干细胞基因组异常，并了解为什么基因组嵌合现象在大脑中普遍存在，但在其他器官中没有。最后，我们的工作可能为研究与染色体不稳定相关的神经发育障碍开辟新的途径。

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.