Regulation of directed neuroblast migration by the ECM and MAB-5/Hox

ECM 和 MAB-5/Hox 对定向神经母细胞迁移的调节

• 批准号: 10689337
• 负责人: Erik A Lundquist
• 金额: $ 35.01万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10689337
• 关键词: Animals; Anterior; Bilateral; Caenorhabditis elegans; Cell Death; Cell division; Cells; Cessation of life; Coupled; Cues; DNA cassette; Data; Development; Embryo; Environment; Extracellular Matrix; Extracellular Structure; Fluorescence-Activated Cell Sorting; Genes; Genetic; Genetic Epistasis; Genomic approach; Goals; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Human; Knowledge; Lateral; Left; Ligands; Mediating; Membrane; Molecular; Muscle; Nervous System Physiology; Neural Crest; Neural Crest Cell; Neurodevelopmental Disorder; Neuronal Differentiation; Neurons; Organ; Pathway interactions; Pattern; Peripheral Nervous System; Phase; Regulation; Role; Science; Signal Pathway; Sorting; Specific qualifier value; System; Techniques; Testing; Tissues; WNT Signaling Pathway; cell motility; cell type; epimerase; extracellular; functional genomics; gain of function; loss of function; migration; mutant; neural circuit; neural network; neuroblast; perlecan; receptor; transcription factor; transcriptome; transcriptome sequencing

Project Summary Directed cell migration is a fundamental morphogenetic mechanism used by animals to build tissues and organs. For example, neural crest cells migrate long distances in the embryo and develop into a plethora of cell types, including the entire peripheral nervous system. In C. elegans, the Q cells are bilateral neuroblasts born in the posterior-lateral region of the animal that undergo left-right asymmetric migration. Initially, QR on the right protrudes and migrates anteriorly, and QL on the left posteriorly. This initial directed migration is regulated by the receptor molecules UNC-40/DCC and PTP-3/LAR, which drive posterior migration. A left-right (L/R) asymmetry in the Q cells results in UNC-40 and PTP-3 being active in QL but not QR, leading to posterior versus anterior migration, respectively. The second phase of migration relies on Wnt signaling and begins after the first Q cell division. QL and descendants encounter a posterior EGL-20/Wnt signal that drives expression of the MAB-5/Hox transcription factor, whereas QR and descendants do not express MAB-5. Further posterior migration of the QL descendants requires MAB-5, which is both necessary and sufficient for posterior Q descendant migration. QL and QR undergo an identical pattern of cell division, migration and cell death to generate three neurons apiece. The phases of Q migration are independent (e.g. in mab-5 mutants, QL initial migration to the posterior is normal, but Q descendants then migrate anteriorly). Our preliminary data indicate that an inherent L/R asymmetry in QL versus QR determines how these cells respond to the extracellular matrix (ECM), which specifies anterior versus posterior migration. Specifically, the Collagenα1XXIV molecule DPY-17 directs posterior migration. DPY-17 is expressed broadly throughout the animal, as opposed to other ECM-related guidance cues (UNC-6/Netrin, SLT-1/Slit) expressed in specific regions to direct migration. Possibly, the structure of the ECM itself provides anterior-posterior guidance information to the Q cells, and UNC-40/DCC and PTP-3/LAR interpret this information. We will test this idea by analyzing DPY-17 and other ECM components in initial Q migration. After initial migration, mab-5/Hox expression in QL directs posterior migration. mab-5/Hox is a terminal selector gene which specifically controls posterior migration and not other aspects of cell division, death, or neuronal differentiation. We will take a functional-genomic approach to define a transcriptional cassette downstream of the MAB-5/Hox terminal selector that directs posterior migration. This proposal utilizes a cutting-edge combination of techniques (e.g. fluorescence-activated cell sorting (FACS) of C. elegans cells and RNA-seq), and leverages the strengths of the C. elegans system in discovery science. It has the potential to significantly advance the goal of achieving a detailed understanding of a simple developmental decision to migrate posteriorly versus anteriorly. Mechanisms used by the Q cells might regulate directed cell migrations involved in neural crest and neurodevelopmental disorders in humans.

项目摘要 定向细胞迁移是动物用来构建组织和细胞的基本形态发生机制 器官。例如，神经脊细胞在胚胎中长距离迁移并发育成过多的细胞。 类型，包括整个外周神经系统。在线虫中，Q细胞是出生的双侧神经母细胞 在经历左右不对称迁移的动物的后外侧区域。最初，QR上的 右侧向前突出和移位，QL向左侧后方突出和移位。这种初始定向迁移受到监管 通过受体分子UNC-40/DCC和PTP-3/LAR驱动后向迁移。A左至右(L/R) Q细胞的不对称性导致UNC-40和PTP-3在QL中活跃，但在QR中不活跃，导致后 而不是前向迁移。迁移的第二阶段依赖于WNT信令，开始于 第一次Q细胞分裂。QL和后代遇到后EGL-20/Wnt信号，驱动 MAB-5/HOX转录因子，而QR及其后代不表达MAB-5。再往后一点 QL后代的迁移需要MAB-5，这对后继Q既是必要的，也是充分的 后代迁徙。QL和QR经历相同的细胞分裂、迁移和细胞死亡模式 每个神经元产生三个神经元。Q迁移的阶段是独立的(例如，在MAB-5突变体中，QL初始 向后迁移是正常的，但Q的后代随后会向前迁移)。 我们的初步数据表明，QL和QR之间固有的L/R不对称决定了这些细胞是如何 对细胞外基质(ECM)做出反应，它规定了前向和后向迁移。具体地说， 胶原蛋白α1XXIV分子DPY-17引导后向迁移。DPY-17在整个 动物，而不是其他与ECM相关的指导线索(UNC-6/Netrin，SLT-1/Sit)，在特定的 区域来引导迁移。可能的是，ECM本身的结构提供了前后引导。 提供给Q单元的信息，UNC-40/DCC和PTP-3/LAR解释这一信息。我们将通过以下方式测试这一想法 分析了DPY-17和其他ECM组分在初始Q偏移中的作用。初始迁移后，MAB-5/HOX QL中的表达指导着后向迁移。MAb-5/Hox是一种末端选择基因，它特异性地控制 后部迁移，而不是细胞分裂、死亡或神经元分化的其他方面。我们将采取一项 用功能基因组学方法确定MAB-5/HOX末端下游的转录盒 指导后方迁移的选择器。这一建议利用了尖端技术组合(例如 线虫细胞的荧光激活细胞分选(FACS)和RNA-SEQ)，并利用 发现科学中的线虫系统。它具有显著推进实现以下目标的潜力 详细了解向后迁移与向前迁移的简单发展决策。 Q细胞使用的机制可能调节涉及神经脊和 人类的神经发育障碍。