Defining human-specific rhombic lip developmental mechanisms

项目摘要 虽然人类小脑传统上与运动功能有关，但最近的研究表明， 小脑的高级大脑功能，如言语，语言，甚至饱腹感。小脑有 在灵长类进化过程中，小脑的体积急剧扩大，因此80%的人类神经元位于小脑。 我们已经确定了一些人类特有的发育特征，这些特征在通常研究的动物中是不存在的。 模型这些特征包括时空扩展的祖细胞区，包括菱形唇， 产生所有的小脑延髓能神经元和一个扩大的心室区，产生GABA能神经元 神经元人类RL是长寿的，存在于整个妊娠期，并表现出相当大的 结构和分子亚结构;在啮齿动物和非人类灵长类动物中未见的特征。独特的 人类小脑的发育特征解释了为什么人类小脑发育模型 疾病是一个挑战。然而，通过研究人类小脑的发育，我们现在已经表明， 菱形唇发育缺陷与人类小脑畸形有关， 蠕虫发育不全，以及毁灭性的小儿脑肿瘤，如髓母细胞瘤。然而，细胞和 驱动小脑菱形唇的人类特异性扩张的分子机制仍然未知。这 这项研究旨在更好地描述整个发育过程中小脑背侧祖细胞区的特征， 免疫组织化学和原位杂交测定的组合。我们还将进行严格的空间 和单细胞转录组分析这一祖细胞区，以确定分子途径驱动其 发展最后，我们将研究人类菱形唇的背景下，小脑畸形，以确定 导致蠕虫发育不全的异常分子程序这项研究利用了我们大量的 在人类和其他动物模型中小脑发育的专业知识，以及 从我们广泛的临床合作者网络中获得的正常和病理人类胎儿组织。

PROJECT SUMMARY While the human cerebellum is traditionally associated with motor functions, recent studies have implicated the cerebellum in higher-order brain functions like speech, language, and even satiety. The cerebellum has dramatically expanded in size across primate evolution so that 80% of human neurons are in the cerebellum. We have identified several human-specific developmental features that are absent in commonly studied animal models. These features include spatiotemporally expanded progenitor zones, including the rhombic lip that produces all cerebellar glutamatergic neurons and an expanded ventricular zone that produces GABAergic neurons. The human RL is long-lived, present throughout the entirety of gestation and exhibits considerable structural and molecular substructure; features not seen in rodents and non-human primates. The unique developmental features of the human cerebellum explains why modeling of human cerebellar developmental disorders has been challenging. However, by studying human cerebellar development, we have now shown that defects in rhombic lip development are implicated in human cerebellar malformations associated with vermian hypoplasia, as well as devastating pediatric brain tumors like Medulloblastoma. Yet, the cellular and molecular mechanisms that drive human-specific expansion of the cerebellar rhombic lip remain unknown. This study aims to better characterize this dorsal cerebellar progenitor zone throughout development using a combination of immunohistochemical and in situ hybridization assays. We will also conduct rigorous spatial and single-cell transcriptome analyses of this progenitor zones to define the molecular pathways driving its development. Lastly, we will study the human rhombic lip in the context of cerebellar malformations to identify aberrant molecular programs contributing to vermian hypoplasia. This study leverages our substantial expertise of cerebellar development in human and other animal models, together with unique samples of normal and pathological human fetal tissue obtained from our extensive network of clinical collaborators.