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Progress in Understanding the Roles of Sphingolipids in Animal Development

Deron Raymond Herr

出版	University of California, San Diego, and San Diego State University, 2004
URL	http://books.google.com.hk/books?id=gvj9s15bS-4C&hl=&source=gbs_api

註釋

The study of the various cellular responses to sphingolipid metabolites has only recently become the subject of widespread interest. These responses are numerous and diverse which suggests important roles of these molecules during development. With few exceptions, most of the knowledge of their mechanisms has been derived from cell culture experiments that lack an appropriate organismal context to understand how these events translate into responses of intact tissues. The purpose of this dissertation is to develop an adequately tractable model system (Drosophila melanogaster) that can be used to manipulate sphingolipid metabolism in a developmentally relevant context. This initial work began by identifying and characterizing a number of Drosophila genes encoding enzymes in this metabolic pathway: sphingosine 1-phosphate lyase (Sply), sphingosine kinase 1 (Sk1), and sphingosine kinase 2 (Sk2). Analysis of Sply and Sk2 mutants revealed gross alterations of sphingolipid content and demonstrated that sphingolipid metabolites are involved in the development and maintenance of muscle and reproductive tissue. Furthermore, gene expression analysis demonstrates that altering sphingolipid content affects the integrity of a number of signal transduction pathways including Notch, Wingless, Hedgehog, and sterol regulatory element binding protein (SREBP). This work also led to the observation that chromosomal location is sufficient to favor coordinate transcriptional regulation of gene pairs, raising the possibility that these genes participate in common cellular functions. This dissertation describes the initiation of an ongoing project to establish the first model system in which sphingolipid metabolism may be precisely manipulated to strategically alter concentrations of individual sphingolipid metabolites in vivo.