Evolutionary mechanisms of neoteny and enlargement of the human cerebral cortex

与其他哺乳动物相比，人类的大脑大大扩大，甚至与我们最近的亲戚，其他类人猿相比。新皮层被认为有助于提高认知能力，因此它的扩大可能是我们作为一个物种成功的主要贡献者。然而，负责这种扩大的进化机制仍不清楚。特别是，在许多人类特有的遗传变化中，哪些是导致大脑皮层扩张的原因尚不清楚。越来越多的证据表明，发育延迟或幼态持续对于增加神经元的产生和大小很重要，但这种延迟是如何产生的也不清楚。在这项提案中，我们将使用人类和非人类猿类大脑类器官来研究这个问题，并揭示哪些遗传位点和发育信号传导过程是人类特定皮质大小确定的关键。我们将使用多组学方法的组合来探测皮质祖细胞在不同阶段的表观遗传和代谢特征，以揭示神经命运的关键调节因子，并确定允许延迟分化从而延长祖细胞扩增的人类特异性变化。我们还将研究由脉络丛分泌的外源性脑脊液来源的信号，脉络丛是一种在人类胎儿大脑中表现出关键发育差异的脑组织。最后，药理学和遗传扰动，包括跨物种遗传位点交换实验，将在功能上测试所确定的调节因子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。这种最先进的类器官、组学和基因工程方法的结合不仅将揭示哪些因素调节时间和细胞命运，还将揭示哪些进化遗传变化是人类大脑扩张的原因。

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.