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.

项目摘要 尽管人类小脑传统上与运动功能有关，但最近的研究暗示了 高阶大脑中的小脑功能，例如语音，语言甚至饱腹感。小脑有 在灵长类动物的演化中，大小急剧扩大，因此80％的人神经元在小脑中。 我们已经确定了一些人类特异性的发育特征，这些特征在经常研究的动物中没有 型号。这些功能包括时空扩展的祖细胞区域，包括菱形嘴唇 产生所有小脑谷氨酸能神经元和产生Gabaergic的膨胀心室区域 神经元。人类RL长期存在，整个妊娠期都存在，并且表现出相当大的 结构和分子下结构；在啮齿动物和非人类灵长类动物中未见的特征。独特 人小脑的发育特征解释了为什么人类小脑发育的建模 疾病一直具有挑战性。但是，通过研究人类小脑的发展，我们现在已经显示 菱形嘴唇发育中的缺陷与人类小脑畸形有关 佛术发育不全以及甲状腺母细胞瘤等毁灭性的小儿脑肿瘤。然而，细胞和 驱动小脑菱形嘴唇的人类特异性扩张的分子机制仍然未知。这 研究旨在通过使用 免疫组织化学和原位杂交测定法的组合。我们还将进行严格的空间 和该祖细胞区域的单细胞转录组分析，以定义驱动其途径的分子途径 发展。最后，我们将在小脑畸形的背景下研究人类菱形唇部，以识别 异常的分子程序导致佛法降低。这项研究利用了我们的实质性 小脑发展的专业知识，以及其他动物模型的专业知识，以及独特的样本 从我们广泛的临床合作者网络获得的正常和病理性的人类胎儿组织。