A conserved Shh cis-regulatory module highlights a common developmental origin of unpaired and paired fins

Nat Genet. 2018 Apr;50(4):504-509. doi: 10.1038/s41588-018-0080-5. Epub 2018 Mar 19.

Abstract

Despite their evolutionary, developmental and functional importance, the origin of vertebrate paired appendages remains uncertain. In mice, a single enhancer termed ZRS is solely responsible for Shh expression in limbs. Here, zebrafish and mouse transgenic assays trace the functional equivalence of ZRS across the gnathostome phylogeny. CRISPR/Cas9-mediated deletion of the medaka (Oryzias latipes) ZRS and enhancer assays identify the existence of ZRS shadow enhancers in both teleost and human genomes. Deletion of both ZRS and shadow ZRS abolishes shh expression and completely truncates pectoral fin formation. Strikingly, deletion of ZRS results in an almost complete ablation of the dorsal fin. This finding indicates that a ZRS-Shh regulatory module is shared by paired and median fins and that paired fins likely emerged by the co-option of developmental programs established in the median fins of stem gnathostomes. Shh function was later reinforced in pectoral fin development with the recruitment of shadow enhancers, conferring additional robustness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animal Fins / growth & development*
  • Animal Fins / metabolism*
  • Animals
  • Animals, Genetically Modified
  • Body Patterning / genetics*
  • CRISPR-Cas Systems
  • Conserved Sequence
  • Enhancer Elements, Genetic
  • Evolution, Molecular
  • Extremities / growth & development
  • Fish Proteins / genetics
  • Hedgehog Proteins / genetics*
  • Humans
  • Mice
  • Mice, Transgenic
  • Oryzias / genetics
  • Oryzias / growth & development
  • Zebrafish / genetics
  • Zebrafish / growth & development
  • Zebrafish Proteins / genetics

Substances

  • Fish Proteins
  • Hedgehog Proteins
  • Zebrafish Proteins