During nervous system development, neurons assemble into distinct structures that are vital for proper brain function. One process essential t this assembly is cell migration;neurons need to migrate from their birthplace to their final destination. For navigation, migrating neurons use guidance cues. However, the regulation of the signaling range of these cues is poorly understood. This project focuses on the attractant chemokine CXCL12. To gain insight into how the distribution of CXCL12 is regulated, this project will (1) determine the distribution and range of CXCL12 signaling and (2) characterize the factors that control the distribution and range of CXCL12 signaling. These studies will be performed in zebrafish embryos, because sophisticated live imaging can be combined with clean genetic approaches. The proposed studies will advance the understanding of CXCL12 signaling and provide general insights into how the distribution of guidance cues is regulated. Abnormalities in human CXCL12 signaling are associated with neuronal and immunological defects and cancer. Thus, the proposed studies have public health significance because they will help to provide the necessary context for understanding human congenital defects and disease.
In the context of the developing vertebrate nervous system, failed neuronal migration or migration to inappropriate locations can cause diseases of the peripheral (e.g. Hirschsprung Disease) and central nervous systems (e.g. Kallmann syndrome and lissencephaly). Additionally, coordinated cell migration plays a critical role in the development of metastatic cancer. CXCL12 signaling, the focus of this proposal, has been implicated in neuron and axon migration, growth of primary tumors and cancer metastasis.
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