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Genesis. 2018 Jan;56(1). doi: 10.1002/dvg.23078. Epub 2017 Oct 27.

Appendages and gene regulatory networks: Lessons from the limbless.

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Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, 85721.
Department of Cellular Biology, University of Georgia, Athens, Georgia, 30602.
Department of Genetics, University of Georgia, Athens, Georgia, 30602.


Among squamate reptiles, dozens of lineages have independently evolved complete or partial limb reduction. This remarkable convergence of limbless and limb-reduced phenotypes provides multiple natural replicates of different ages to explore the evolution and development of the vertebrate limb and the gene regulatory network that controls its formation. The most successful and best known of the limb-reduced squamates are snakes, which evolved a limb-reduced body form more than 100 million years ago. Recent studies have revealed the unexpected finding that many ancient limb enhancers are conserved in the genomes of snakes. Analyses in limbed animals show that many of these limb enhancers are also active during development of the phallus, suggesting that these enhancers may have been retained in snakes due their importance in regulating transcription in the external genitalia. This hypothesis is substantiated by functional tests of snake enhancers, which demonstrate that snake enhancer elements have lost limb function while retaining genital enhancer function. The large degree of overlap in the gene regulatory networks deployed during limb and phallus development may act to constrain the divergence of shared gene network components and the evolution of appendage morphology. Future studies will reveal whether limb regulatory elements have undergone similar functional changes in other lineages of limb-reduced squamates.


enhancer; limb; lizard; snake; squamate

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