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Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):12027-12032. doi: 10.1073/pnas.1710254114. Epub 2017 Oct 23.

Alk and Ltk ligands are essential for iridophore development in zebrafish mediated by the receptor tyrosine kinase Ltk.

Author information

1
Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520.
2
Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520; Joseph.Schlessinger@yale.edu stefania.nicoli@yale.edu.
3
Section of Cardiology, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT 06511.

Abstract

Anaplastic lymphoma kinase (Alk) and leucocyte tyrosine kinase (Ltk) were identified as "orphan" receptor tyrosine kinases (RTKs) with oncogenic potential. Recently ALKAL1 and ALKAL2 (also named "augmentor-β" and "augmentor-α" or "FAM150A" and "FAM150B," respectively) were discovered as physiological ligands of Alk and Ltk. Here, we employ zebrafish as a model system to explore the physiological function and to characterize in vivo links between Alk and Ltk with their ligands. Unlike the two ligands encoded by mammalian genomes, the zebrafish genome contains three genes: aug-α1, aug-α2, and aug-β Our experiments demonstrate that these ligands play an important role in zebrafish pigment development. Deficiency in aug-α1, aug-α2, and aug-β results in strong impairment in iridophore patterning of embryonic and adult zebrafish that is phenocopied in zebrafish deficient in Ltk. We show that aug-α1 and aug-α2 are essential for embryonic iridophore development and adult body coloration. In contrast, aug-α2 and aug-β are essential for iridophore formation in the adult eye. Importantly, these processes are entirely mediated by Ltk and not by Alk. These experiments establish a physiological link between augmentor ligands and Ltk and demonstrate that particular augmentors activate Ltk in a tissue-specific context to induce iridophore differentiation from neural crest-derived cells and pigment progenitor cells.

KEYWORDS:

cell signaling; cytokines; phosphorylation; pigment development; surface receptors

PMID:
29078341
PMCID:
PMC5692561
DOI:
10.1073/pnas.1710254114
[Indexed for MEDLINE]
Free PMC Article

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