Defining human-specific rhombic lip developmental mechanisms

定义人类特有的菱形唇发育机制

• 批准号: 10723088
• 负责人: Parthiv Haldipur
• 金额: $ 54.15万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723088
• 关键词: ATAC-seq; Address; Animal Model; Atlases; Automobile Driving; Biological Assay; Biology; Birth; Brain; Brush Cell; Cell Nucleus; Cells; Cerebellar Diseases; Cerebellar Nuclei; Cerebellar malformation; Cerebellar vermis structure; Cerebellum; Chick; Childhood Brain Neoplasm; Clinical; Complement; Conceptions; Congenital Abnormality; Congenital cerebellar hypoplasia; Cytoplasmic Granules; Dandy-Walker Syndrome; Data; Defect; Development; Diagnosis; Disease; Dorsal; Embryo; Evolution; Exhibits; Genes; Glutamates; Goals; Grant; Growth; Histologic; Human; Immunohistochemistry; In Situ; In Situ Hybridization; Knowledge; Language; Lead; Lip structure; Lobe; Macaca; Maintenance; Maps; Methodology; Mitotic; Molecular; Morphology; Motor; Mus; Neuronal Differentiation; Neurons; Pathogenesis; Pathologic; Pathway interactions; Phase; Pregnancy; Primates; Production; Proliferating; Rodent; Sampling; Satiation; Specificity; Speech; Study models; Testing; Tissues; Ventricular; Work; cell type; design; developmental disease; experimental study; fetal; genome-wide; granule cell; human fetus tissue; human model; imaging study; improved; medulloblastoma; mouse model; nonhuman primate; novel; progenitor; programs; self-renewal; spatiotemporal; stem cells; subventricular zone; transcriptome; transcriptome sequencing; transcriptomics

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.

项目概要 虽然人类小脑传统上与运动功能相关，但最近的研究表明 小脑负责高级大脑的功能，如言语、语言，甚至饱腹感。小脑有 在灵长类动物的进化过程中，小脑的大小急剧扩大，因此 80% 的人类神经元都位于小脑中。 我们已经确定了几种人类特有的发育特征，而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区，包括菱形唇 产生所有小脑谷氨酸能神经元和扩大的脑室区，产生 GABA 能 神经元。人类 RL 寿命很长，存在于整个妊娠期，并且表现出相当大的 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要建立人类小脑发育模型 疾病一直具有挑战性。然而，通过研究人类小脑的发育，我们现在已经证明 菱形唇发育缺陷与人类小脑畸形有关 蚓发育不全，以及毁灭性的儿童脑肿瘤，如髓母细胞瘤。然而，蜂窝和 驱动人类特有的小脑菱形唇扩张的分子机制仍然未知。这 研究旨在使用 免疫组织化学和原位杂交检测相结合。我们还将进行严格的空间 以及该祖区的单细胞转录组分析，以确定驱动其的分子途径 发展。最后，我们将在小脑畸形的背景下研究人类菱形唇，以确定 导致蚓发育不全的异常分子程序。这项研究利用了我们大量的 人类和其他动物模型小脑发育的专业知识，以及独特的样本 从我们广泛的临床合作者网络中获得的正常和病理性人类胎儿组织。