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

项目总结

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.