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 定向细胞迁移是一种基本的形态发生机制，用于建立组织和 器官。例如，神经rest细胞在胚胎中迁移长距离，并发展成众多细胞 类型，包括整个周围神经系统。在秀丽隐杆线虫中，Q细胞是双侧神经细胞出生的 在动物的后外侧区域，经历了左右不对称迁移。最初，QR在 右突出并向前迁移，左侧向左侧。最初的定向迁移受到调节 通过受体分子UNC-40/DCC和PTP-3/LAR，驱动后迁移。左右（L/R） Q细胞中的不对称性导致UNC-40和PTP-3在QL中活跃，而不是QR，导致后部 分别与前迁移。迁移的第二阶段依赖于Wnt信令，然后开始 第一个Q细胞分裂。 QL和后代遇到后EGL-20/Wnt信号，该信号驱动表达 MAB-5/HOX转录因子，而QR和后代不表达MAB-5。进一步的后部 QL后代的迁移需要MAB-5，这对于后Q是必要且足够的 后代迁移。 QL和QR经历了相同的细胞分裂模式，迁移和细胞死亡的模式 产生三个神经元的猿。 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，但是Q后代然后向前迁移）。 我们的初步数据表明，QL与QR的继承L/R不对称确定了这些单元 对细胞外基质（ECM）的反应，该基质指定前迁移与后迁移。具体来说， 胶原蛋白α1XXIV分子DPY-17指导后迁移。 DPY-17在整个过程中广泛表达 动物，与其他与ECM相关的指导提示（UNC-6/Netrin，SLT-1/SLIT）相反 直接迁移的地区。可能，ECM本身的结构提供了前后指导 信息到Q单元，以及UNC-40/DCC和PTP-3/LAR解释此信息。我们将通过 在初始Q迁移中分析DPY-17和其他ECM组件。初始迁移后，mab-5/hox QL中的表达指导后迁移。 MAB-5/HOX是一个末端选择器基因，专门控制 后迁移，而不是细胞分裂，死亡或神经元分化的其他方面。我们将接受 功能基因组方法来定义MAB-5/HOX终端下游的转录盒 指导后迁移的选择器。该提案利用了技术的尖端组合（例如 秀丽隐杆线虫细胞和RNA-seq的荧光激活细胞分选（FACS），并利用强度 发现科学中的秀丽隐杆线虫系统。它有可能大大提高实现目标的目标 对简单的发展决定的详细理解，即向后迁移和反向迁移。 Q细胞使用的机制可能会调节涉及神经rest的定向细胞迁移和 人类的神经发育障碍。