Integration of cellular, molecular and mathematical investigation of the evolution of early telencephalon organisation

早期端脑组织进化的细胞、分子和数学研究的整合

• 批准号: 2578150
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2578150
• 关键词: Integration; cellular; molecular; mathematical; investigation

One important step in forebrain development is the establishment of a stereotyped dorsalpallium (giving rise to cortical excitatory projection neurons) and the ventral subpallium(producing all telencephalic inhibitory interneurons). This determines the initialexcitatory/inhibitory balance of progenitors and imposes the future size of the brainhemispheres.Although the signals controlling this DV organisation and the downstream effectors drivingdifferentiation and morphogenesis are conserved across vertebrates, little is known on thespatiotemporal modulation of these players across species. Yet, this modulation is a motor ofevolutionary divergence in brain complexity. This project aims to understand the evolutionaryspatiotemporal modulation of signalling networks during early telencephalon development.Under the supervision of CH, the student will analyse the dynamics of Hh and Wnt signallingactivity along the DV axis in zebrafish, mouse and human telencephalon from onset of neuralclosure to early neurogenesis. This work will combine in situ staining and transcriptomedatasets from tissue and from mouse and human 3D culture. The 3D culture will be exposedto polarised signals (Hh or Wnt) using biomaterial (cryogels) optimised by the BN team.Under ZH supervision, the datasets will be used to identify a restricted set of parametersdescribing the central components of the signalling network at play and to construct adynamic model of spatiotemporal telencephalic DV organisation. This model will generate thebehaviour of the three species characterised above as well as deliver predictions on thesignalling dynamic across evolution. Some of these predictions will then be verified by thestudent in CH lab, by tissue staining and functional experiments in mouse and fish.Both sides of the proposal will be run in parallel, will deliver novel findings and develop apractical/theoretical dynamic framework that will have a lasting impact on the field ofdevelopmental neuroscience.

前脑发育的一个重要步骤是建立定型的背侧大脑皮层（产生皮质兴奋性投射神经元）和腹侧大脑皮层下层（产生所有端脑抑制性中间神经元）。这决定了祖细胞最初的兴奋/抑制平衡，并影响了大脑半球的未来大小。尽管控制这种 DV 组织的信号以及驱动分化和形态发生的下游效应器在脊椎动物中是保守的，但人们对这些参与者在不同物种之间的时空调节知之甚少。然而，这种调节是大脑复杂性进化分歧的动力。该项目旨在了解早期端脑发育过程中信号网络的进化时空调节。在CH的监督下，学生将分析斑马鱼、小鼠和人类端脑从神经闭合开始到早期神经发生沿DV轴的Hh和Wnt信号传导活动的动态。这项工作将结合来自组织以及小鼠和人类 3D 培养物的原位染色和转录组数据集。 3D 培养物将使用 BN 团队优化的生物材料（冷冻凝胶）暴露于极化信号（Hh 或 Wnt）。在 ZH 监督下，数据集将用于识别一组限制参数，描述正在发挥作用的信号网络的中心组件，并构建时空端脑 DV 组织的动态模型。该模型将生成上述三个物种的行为，并提供对整个进化过程中信号动态的预测。其中一些预测将由CH实验室的学生通过组织染色和小鼠和鱼的功能实验来验证。该提案的双方将并行进行，将提供新的发现并开发一个实践/理论的动态框架，这将对发育神经科学领域产生持久的影响。