Distant Insulin Signaling Regulates Vertebrate Pigmentation through the Sheddase Bace2

Publication date: Available online 24 May 2018
Source:Developmental Cell
Author(s): Yan M. Zhang, Milena A. Zimmer, Talia Guardia, Scott J. Callahan, Chandrani Mondal, Julie Di Martino, Toshimitsu Takagi, Myles Fennell, Ralph Garippa, Nathaniel R. Campbell, Jose Javier Bravo-Cordero, Richard M. White
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.

Graphical abstract

Teaser

Zhang et al. demonstrate that insulin signaling affects pigment patterning in zebrafish. They show that the local response to insulin signaling is regulated by Bace2, a melanocyte-enriched sheddase that cleaves the insulin receptor.


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