Distant Insulin Signaling Regulates Vertebrate Pigmentation through the Sheddase Bace2

Abstract

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.

Galanin Signaling in the Brain Regulates Color Pattern Formation in Zebrafish

“…Insulin signaling is another endocrine pathway known to affect pigment cell development and behavior: overactive insulin b signaling in melanophores results in over-proliferation and hyperdendritic cells [24]. While we see similar melanophore shape defects in npm mutants ( Figure S1), we detected no change of insb expression in the mutants ( Figure S4B).…”

“…Whereas agouti/melanocortin receptor signaling controls dorso-ventral counter shading [23], insulin and thyroid hormone signaling affect stripe formation. Insulin signaling needs to be specifically attenuated in melanophores by the sheddase Bace2 to ensure proper stripe formation [24]. Lack of thyroid hormone leads to an excess of melanophores, while xanthophores remain in a cryptic unpigmented state.…”

Melanophores Tune Out the Noise to Make Stripes

“…With few exceptions (Rawls and Johnson, 2003;Svetic et al, 2007), controls of early larval melanophore morphogenesis have been mysterious. In this issue of Developmental Cell, Zhang et al (2018) use the zebrafish mutant wanderlust to reveal a pathway affecting melanophore morphogenesis, as well as an unexpected impact of endocrine, rather than paracrine, signaling (Figure 1).…”

“…Examining how Bace2 affects zebrafish melanophores, Zhang et al (2018) first demonstrated that it acts cell-autonomously in the melanophores as they differentiate. To find the relevant target, the authors performed a chemical genetic screen for suppressors of the bace2 mutant phenotype.…”

“…Given that Bace2 regulates insulin receptor trafficking in pancreatic cells (Casas et al, 2010), Zhang et al (2018) hypothesized, and then showed, that Bace2 targets the insulin receptor for cleavage in melanophores. This suggested that Bace2 mutations-which cause aberrant receptor activity-render melanophores more sensitive to insulin.…”