Distant Insulin Signaling Regulates Vertebrate Pigmentation Through the Sheddase Bace2

Dev Cell. 2018 Jun 4;45(5):580-594.e7. doi: 10.1016/j.devcel.2018.04.025. Epub 2018 May 24.


Patterning of vertebrate melanophores is essential for mate selection and protection from UV-induced damage. Patterning can be influenced by circulating long-range factors, such as hormones, but it is unclear how their activity is controlled in recipient cells to prevent excesses in cell number and migration. The zebrafish wanderlust mutant harbors a mutation in the sheddase bace2 and exhibits hyperdendritic and hyperproliferative melanophores that localize to aberrant sites. We performed a chemical screen to identify suppressors of the wanderlust phenotype and found that inhibition of insulin/PI3Kγ/mTOR signaling rescues the defect. In normal physiology, Bace2 cleaves the insulin receptor, whereas its loss results in hyperactive insulin/PI3K/mTOR signaling. Insulin B, an isoform enriched in the head, drives the melanophore defect. These results suggest that insulin signaling is negatively regulated by melanophore-specific expression of a sheddase, highlighting how long-distance factors can be regulated in a cell-type-specific manner.

Keywords: PI3K; bace2; insulin; insulin receptor; mTOR; melanocyte; melanophore; pigment patterning; zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Body Patterning*
  • Cell Movement / physiology
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / physiology
  • Gene Expression Regulation, Developmental
  • Insulin / genetics
  • Insulin / metabolism*
  • Melanophores / cytology
  • Melanophores / physiology*
  • Mutation
  • Phenotype
  • Phosphatidylinositol 3-Kinases
  • Pigmentation*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Zebrafish / embryology
  • Zebrafish / physiology*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*


  • Insulin
  • Zebrafish Proteins
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Amyloid Precursor Protein Secretases
  • BACE2 protein, zebrafish