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Distant Insulin Signaling Regulates Vertebrate Pigmentation through the Sheddase Bace2

2018; Elsevier BV; Volume: 45; Issue: 5 Linguagem: Inglês

10.1016/j.devcel.2018.04.025

1878-1551

Yan M. Zhang, Milena A. Zimmer, Talia Guardia, Scott J. Callahan, Chandrani Mondal, Julie S. Di Martino, Toshimitsu Takagi, Myles Fennell, Ralph Garippa, Nathaniel R. Campbell, Jose Javier Bravo‐Cordero, Richard M. White,

Plant Molecular Biology Research

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.