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The fruit fly embryo is divided into segments by a cascade of genes that act in sequence, each tier refining the pattern set by the one before. Maternal gradients such as Bicoid and Nanos regulate gap genes, which are expressed in broad bands; gap genes regulate pair-rule genes, expressed in seven stripes; pair-rule genes regulate segment polarity genes, expressed in fourteen stripes, one per segment. Homeotic (Hox) genes then give each segment its identity. Christiane Nüsslein-Volhard and Eric Wieschaus identified many of these genes in a genetic screen published in 1980, and they shared the 1995 Nobel Prize in Physiology or Medicine with Edward B. Lewis.
Show the expression pattern of each tier on a cartoon embryo, side by side, and then show the larval cuticle of a mutant from each class. Ask students to predict the missing pattern from the expression domain. The even-skipped stripe 2 enhancer makes a good worked example of how broad gradients are converted into a sharp stripe.
A fruit fly larva has a clear series of segments: several head segments fused together, three thoracic segments and eight abdominal segments. How does a single oval egg turn into this repeating pattern? Drosophila provided the first detailed answer.
In the late 1970s Christiane Nüsslein-Volhard and Eric Wieschaus, working in Heidelberg, mutated flies on a large scale and looked for embryos with abnormal segment patterns. They found mutants that fell into a few clear classes, and the classes corresponded to steps in a hierarchy.
The hierarchy begins before fertilization. The mother deposits bicoid mRNA at the anterior pole of the egg and nanos mRNA at the posterior. In the early embryo, nuclei divide many times without forming cell membranes, creating a syncytium. Bicoid protein spreads from the front through the shared cytoplasm, forming a gradient. Nanos protein at the back blocks translation of maternal hunchback mRNA there.
These maternal gradients regulate the gap genes, including hunchback, Krüppel, knirps and giant. Each is expressed in one or two broad bands. A gap mutant lacks several neighboring segments.
Gap proteins regulate the pair-rule genes, such as even-skipped, fushi tarazu and hairy. These are expressed in seven stripes. The stripes arise because the pair-rule genes carry separate enhancers that each read a different local mix of gap proteins. The even-skipped stripe 2 enhancer is a classic case. Bicoid and Hunchback activate it, Giant represses it from the front and Krüppel represses it from behind, so it is active only in a narrow band. Pair-rule mutants lose pattern in alternating segment-width regions.
Pair-rule proteins then regulate the segment polarity genes, such as engrailed, wingless and hedgehog, which form fourteen stripes. By this time cell membranes have formed. Cells expressing engrailed and cells expressing wingless sit next to each other at each boundary and keep each other's expression going through the secreted signals Hedgehog and Wingless. Segment polarity mutants have part of every segment replaced by a mirror-image copy of another part.
With boundaries set, Hox genes, the homeotic selector genes studied by Edward B. Lewis, assign each segment its identity. Their expression is also set by gap and pair-rule proteins.
The fly hierarchy shows a general principle of development: smooth gradients are read by combinations of transcription factors, through modular enhancers, to produce sharp and repeated patterns. Many of these gene families, such as hedgehog and wingless (Wnt), are used in vertebrate development as well.
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