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: 10469982
• 负责人: Erik A Lundquist
• 金额: $ 35.03万
• 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/10469982
• 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; Molecular; Muscle; Nervous System Physiology; Neural Crest; Neural Crest Cell; Neurodevelopmental Disorder; Neuronal Differentiation; Neurons; Organ; Pathway interactions; Pattern; Peripheral Nervous System; Phase; Q-Sort; Regulation; Role; Science; Signal Pathway; Sorting - Cell Movement; 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.

项目概要 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，神经嵴细胞在胚胎中长距离迁移并发育成大量细胞 类型，包括整个周围神经系统。在秀丽隐杆线虫中，Q 细胞是双侧神经母细胞 在动物的后外侧区域，进行左右不对称迁移。最初，QR 右侧突出并向前移动，左侧的 QL 向后移动。这种最初的定向迁移受到监管 由受体分子 UNC-40/DCC 和 PTP-3/LAR 驱动，驱动后部迁移。 A 左-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，从而导致后部 分别与前移相比。迁移的第二阶段依赖于 Wnt 信号传导，并在 第一次Q细胞分裂。 QL 和后代遇到后部 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 QL 后代的迁移需要 MAB-5，这对于后 Q 来说既是必要的也是充分的 后裔迁徙。 QL 和 QR 经历相同的细胞分裂、迁移和细胞死亡模式 每个生成三个神经元。 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 后代则向前迁移）。 我们的初步数据表明，QL 与 QR 中固有的 L/R 不对称性决定了这些细胞如何 对细胞外基质 (ECM) 做出反应，该基质指定前向与后向迁移。具体来说， 胶原α1XXIV 分子 DPY-17 指导向后迁移。 DPY-17 在整个组织中广泛表达 动物，而不是其他以特定方式表达的 ECM 相关指导线索（UNC-6/Netrin、SLT-1/Slit） 直接移民的地区。 ECM 本身的结构可能提供前后引导 信息传递给 Q 细胞，UNC-40/DCC 和 PTP-3/LAR 解释该信息。我们将通过以下方式测试这个想法 分析初始 Q 迁移中的 DPY-17 和其他 ECM 成分。初始迁移后，mab-5/Hox QL 中的表达指导后向迁移。 mab-5/Hox 是一个末端选择基因，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。我们将采取一个 功能基因组方法定义 MAB-5/Hox 终端下游的转录盒 指导后迁移的选择器。该提案采用了尖端技术组合（例如 线虫细胞的荧光激活细胞分选 (FACS) 和 RNA-seq），并利用了 发现科学中的线虫系统。它有可能显着推进实现 详细了解向后迁移与向前迁移的简单发育决定。 Q 细胞使用的机制可能调节参与神经嵴和神经嵴的定向细胞迁移 人类神经发育障碍。