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20 Transcriptional Regulation by Homeodomain Proteins: Structural, Functional, and Genetic Aspects

Kurt Wüthrich, Walter Gehring


The introductory section presents an account of the discovery of the homeobox and the homeodomain, and their distribution and evolutionary conservation. A description of the three-dimensional structure of the homeodomain and its binding mode in complexes with DNA then provides the basis for a discussion on mechanistic aspects of transcriptional regulation by homeodomain proteins. An appendix gives a brief introduction to the use of nuclear magnetic resonance (NMR) spectroscopy for three-dimensional structure determination of proteins and protein-DNA complexes at atomic resolution.

Early History Leading to the Identification of the Homeobox
In 1934, Thomas H. Morgan proposed the theory of differential gene activity, which states that in each cell of a multicellular organism only a specific set of genes, rather than the entire genome, is active and that differential gene activity controls cell differentiation and development (Morgan 1934). On the basis of embryological experiments, he suggested that the initial differences may reside in different regions of the egg cytoplasm and that they affect the activity of the genes in those nuclei which become associated with the respective cytoplasmic regions. The activated genes would in turn affect the cytoplasm, thereby initiating a new series of reciprocal nucleo-cytoplasm interactions. This theory has gained strong support during the last 60 years and forms the basis of our thinking about the genetic control of development. The orderly process of development is based on the coordinated and concerted action of thousands of genes in a precise spatial and temporal pattern and requires regulatory circuits...

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