期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：45
页码：12027-12032
DOI：10.1073/pnas.1710254114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
