Evolutionary mechanisms of neoteny and enlargement of the human cerebral cortex

人类大脑皮层幼态持续和扩大的进化机制

• 批准号: EP/Z000718/1
• 负责人: Madeline Lancaster
• 金额: $ 221.7万
• 依托单位: MRC Laboratory of Molecular Biology
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FZ000718%2F1
• 关键词: Evolutionary; mechanisms; neoteny; enlargement; human

The human brain is greatly enlarged compared with other mammals and even our closest living relatives, the other great apes. The neocortex is thought to contribute to higher cognitive capabilities, and as such its enlargement is likely a major contributor to our success as a species. However, the evolutionary mechanisms responsible for this enlargement are still unclear. In particular, which of the many human-specific genetic changes are responsible for expansion of the cerebral cortex are unknown. Increasing evidence points to a delay in development, or neoteny, as being important for enabling increased neuron production and size, yet how that delay comes about is also not known. In this proposal, we will use human and nonhuman ape cerebral organoids to examine this question and to uncover which genetic loci and developmental signalling processes have been key to human-specific cortical size determination. We will use a combination of multi-omics approaches to probe the epigenetic and metabolic signatures of cortical progenitors at various stages, to reveal key regulators of neural fate and identify human-specific changes that allow for delayed differentiation and thus protracted progenitor expansion. We will also investigate extrinsic, cerebrospinal fluid derived signals secreted by the choroid plexus, a brain tissue exhibiting key developmental differences in the human fetal brain. Finally, pharmacological and genetic perturbations, including cross-species genetic locus swapping experiments, will functionally test whether the identified regulators and their relevant human-specific genetic changes have a causal role in progenitor and neuron expansion. This combination of state-of-the-art organoid, omics, and genetic engineering approaches will reveal not only which factors regulate timing and cell fate, but also which evolutionary genetic changes are responsible for human brain expansion.

与其他哺乳动物，甚至我们最亲近的亲戚，其他伟大的猿类相比，人的大脑大大扩大。新皮层被认为有助于更高的认知能力，因此，其扩大很可能是我们作为一种物种成功的主要贡献者。但是，尚不清楚导致这种扩大的进化机制。特别是，许多人类特异性遗传变化中的哪个是造成大脑皮层扩张的原因是未知的。增加证据表明发育迟缓或新质体对于使神经元的产生和大小增加很重要，但是延迟的产生也尚不清楚。在此提案中，我们将使用人类和非人类猿的脑囊体来检查这个问题，并发现哪些遗传基因座和发育信号传导过程已经是人类特异性皮质大小的关键。我们将使用多摩学方法的组合来探测各个阶段皮质祖细胞的表观遗传和代谢特征，以揭示神经命运的关键调节剂并识别人类特异性变化，从而允许延迟分化并因此延伸祖先的扩张。我们还将研究由脉络丛分泌的外在的，脑脊液衍生的信号，该信号是一种脑组织，在人胎儿脑中表现出关键的发育差异。最后，包括跨物种遗传基因座交换实验在内的药理学和遗传扰动将在功能上测试已鉴定的调节剂及其相关的人类特异性遗传变化是否在祖细胞和神经元扩张中具有因果作用。最先进的器官，OMIC和遗传工程方法的结合不仅会揭示哪些因素调节时间和细胞命运，还可以揭示哪些进化遗传变化导致人脑扩展。