The notion that particular genes can influence the establishment of distinct regions in an embryo arose from efforts to catalog single-gene mutations that affect development of the fruit fly Drosophilia. In the 1960s and 70s, E.B. Lewis at the California Institute of Technology reported a number of mutations that resulted in either the duplication of a distinct body segment or the appearance of an inappropriate structure at an ectopic location in the fly. Subsequently, studies by C. Nusslein-Volhard and E. Wieschaus demonstrated the existence of numerous such "master control" genes, each forming part of a cascade of gene expression leading to segmentation of the developing embryo.

Homeotic genes code for DNA-binding proteins (transcription factors) that bind to a distinctive sequence of genomic DNA called the homeobox. Similar genes have been found in many species. Using an approach known as cloning by homology, at least four "clusters" of homeobox genes have been identified in frogs, mice, and humans, among others. The genes of each cluster are closely, but not consecutively, spaced on a single chromosome. Other motifs identified in Drosophilia have led to the discovery of additional families of DNA-binding proteins, which have again been found in a variety of species.

A number of developmental anomalies in mice and humans have turned out to be mutations in homeotic or other developmental control genes initially identified in the fly. These include genes for several human congenital abnormalities of the central and peripheral nervous system, including DiGeorge syndrome and Waardenburg's syndrome. DiGeorge syndrome is caused by a mutation in the Hox-1.3 gene; the disease affects peripheral and central nervous system morphogenesis and neural crest migration. Waardenburg's syndrome is caused by a mutation in the Pax-3 gene. The disease affects the inner ear and several regions of the brain.

Neuroscience, Sinaur Associates (QP355.2.N487 1997)

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