Signaling pathways that regulate scaling and regeneration of the cerebellum

小脑由人类大脑中80%的神经元组成，参与平衡和运动。 协调，并通过其前脑回路调节语言、推理和社交过程。这个 发育中的小脑对出生前后影响生长(或造成伤害)的因素特别敏感， 因为它的大部分生长发生在妊娠晚期，并在出生后继续。出生后小脑皮质 有两个增殖的干/祖细胞群体，一个致力于制造兴奋性颗粒细胞，以及 除了中间神经元和星形胶质细胞。鉴于在定义 生成发育中的小脑的干细胞/祖细胞和谱系，对其能力知之甚少。 小脑在受伤后产生新的细胞。我们最近发现，小鼠的小脑有一个 大容量补充出生前后死亡的细胞。首先，我们发现表达巢蛋白的前体细胞(Net) 通常专属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)后者通过辐射或遗传方法致死。此外，至少有两个空间和 受血统限制的转录上不同的NEP亚型对GCP的丢失有不同的反应 以实现损伤后细胞类型的适当缩放。第二，浦肯野细胞(PC)，由胚胎出生 13.5天，通过PC杀伤后罕见的未成熟浦肯野细胞(IPC)的增殖而迅速被取代，以及 个人电脑的补给与年龄有关。最后，死亡细胞释放的信号，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 我们每一个受伤的模型。我们将解决两种损伤的两个关键问题：i)什么是基因 表达变化是细胞补充所必需的细胞过渡的基础，以及ii)什么是 死亡细胞、免疫细胞和神经胶质细胞在再生中的作用。我们的中心假设是小脑祖细胞 稀有的未成熟神经元保持着明显的转录可塑性，并与 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 使用单细胞和突变分析的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。

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.