Signaling pathways that regulate scaling and regeneration of the cerebellum

调节小脑缩放和再生的信号通路

• 批准号: 9885450
• 负责人: ALEXANDRA L. JOYNER
• 金额: $ 50.65万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9885450
• 关键词: Address; Astrocytes; Biological Models; Birth; Brain; Candidate Disease Gene; Cell Death; Cell Lineage; Cell Nucleus; Cells; Cerebellar Cortex; Cerebellum; Clinical; Cognition; Complication; Computing Methodologies; Development; Embryo; Environmental Risk Factor; Equilibrium; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Growth; Human; Image; Immune; Injury; Interneurons; Label; Language; Language Development; Lead; Lobule; Microglia; Modeling; Molecular; Motor; Mus; Mutate; Natural regeneration; Neonatal; Neurodevelopmental Problem; Neuroglia; Neurons; Newborn Infant; Output; Paper; Pathway interactions; Performance; Perinatal; Population; Premature Birth; Production; Proliferating; Prosencephalon; Publishing; Purkinje Cells; Reactive Oxygen Species; Recovery; Regenerative response; Regulator Genes; Resolution; Risk Factors; Role; SHH gene; Signal Pathway; Signal Transduction; Slice; Social Development; Social Functioning; Social Processes; System; Techniques; Testing; Third Pregnancy Trimester; Time; Transgenic Mice; Validation; Work; age related; autism spectrum disorder; base; cell behavior; cell killing; cell type; cognitive development; experimental study; functional gain; genetic approach; genetic signature; granule cell; insight; irradiation; loss of function; mutant; neonatal brain; nestin protein; novel; postnatal; precursor cell; progenitor; repaired; response; response to injury; single cell analysis; single-cell RNA sequencing; stem; stem cells; therapy development; white matter

The cerebellum, consisting of 80% of the neurons in the human brain, is involved in balance and motor coordination, and also modulates language, reasoning and social processes via its forebrain circuits. The developing cerebellum is particularly sensitive to factors that impact on growth (or cause injury) around birth, since much of its growth occurs in the third trimester and continues after birth. The postnatal cerebellar cortex has two proliferating stem/progenitor populations, one dedicated to making excitatory granule cells and the other to interneurons and astrocytes. Whereas great advances have been made in defining the stem/progenitor cells and lineages that generate the developing cerebellum, little is known about the ability of the cerebellum to produce new cells following injury. We recently discovered that the mouse cerebellum has a large capacity to replenish cells killed around birth. First, we found that Nestin-expressing progenitors (NEPs) that normally are dedicated to the astrocyte lineage are reprogrammed to become granule cell precursors (GCPs) when the latter are killed by irradiation or genetic approaches. Furthermore, at least two spatially and transcriptionally distinct NEP subtypes that are lineage-restricted have different responses to the loss of GCPs to achieve proper scaling of cell types after injury. Second, Purkinje cells (PCs), which are born by embryonic day 13.5, are rapidly replaced via proliferation of rare immature Purkinje cells (iPCs) following PC killing, and replenishment of PCs is age-dependent. Finally, signals released by dying cells, such as reactive oxygen species (ROS), and cells in the microenvironment can have critical influences on repair responses of progenitor cells. Preliminary results showed that cells in microenvironment have distinct cellular responses in each of our injury models. We will address two critical questions for both injuries: i) What are the gene expression changes that underlie the cellular transitions necessary for cell replenishment and ii) what are the roles of dying cells, immune cells and glia in regeneration. Our central hypothesis is that cerebellar progenitors and rare immature neurons maintain distinct transcriptional plasticity and along with cells in the microenvironment respond differently to killing of GCPs and PCs. Our specific aims are to: 1) Uncover the transcriptional signatures of NEP subtypes and iPCs during development and regeneration, and identify pathways required for proliferation and neuron production using single cell and mutant analyses. 2) Determine how the microenvironment influences NEP and iPC injury responses.

小脑由人脑中80%的神经元组成，与平衡和运动有关 协调，也通过前脑回路调节语言，推理和社会过程。的 发育中的小脑对出生前后影响生长（或导致损伤）的因素特别敏感， 因为它的大部分生长发生在第三个三个月，并在出生后继续。出生后的小脑皮质 有两个增殖的干/祖细胞群，一个致力于制造兴奋性颗粒细胞， 其他的是中间神经元和星形胶质细胞。尽管在定义 干/祖细胞和谱系，产生发展小脑，很少有人知道的能力， 小脑在受伤后产生新的细胞。我们最近发现老鼠的小脑 大容量补充出生时死亡的细胞。首先，我们发现表达巢蛋白的祖细胞（NEPs） 通常专用于星形胶质细胞谱系的细胞被重新编程为颗粒细胞前体 （GCP），当后者被辐射或遗传方法杀死时。此外，至少两个空间和 受谱系限制的转录上不同的NEP亚型对GCPs的缺失有不同的反应 以实现损伤后细胞类型的适当缩放。第二，浦肯野细胞（Purkinje cells，PCs），由胚胎干细胞产生。 第13.5天，在PC杀死后，通过罕见的未成熟浦肯野细胞（iPC）的增殖迅速替换，和 个人电脑的补充取决于年龄。最后，垂死细胞释放的信号，如活性氧 物种（ROS）和微环境中的细胞可以对修复反应产生关键影响。 祖细胞初步结果表明，微环境中的细胞在细胞内具有不同的细胞反应， 我们的每一个受伤模型我们将解决两个关键问题的伤害：i）什么是基因 表达的变化是细胞补充所必需的细胞转换的基础，以及ii） 垂死细胞、免疫细胞和神经胶质在再生中的作用。我们的核心假设是小脑祖细胞 和罕见的未成熟神经元保持独特的转录可塑性，并沿着细胞中， 微环境对杀死GCP和PC的反应不同。我们的具体目标是：1）发现 NEP亚型和iPC在发育和再生过程中的转录特征，并鉴定 使用单细胞和突变体分析增殖和神经元产生所需的途径。2)确定 微环境如何影响NEP和iPC损伤反应。