ALKALs are in vivo ligands for ALK family receptor tyrosine kinases in the neural crest and derived cells

Significance Neuroblastoma is a pediatric tumor arising from the neural crest. Dysregulation of the receptor tyrosine kinase ALK has been linked to neuroblastoma, making it important to understand its function in native conditions. In zebrafish, a related receptor—Ltk—is also expressed in neural crest and regulates development of specific pigment cells—iridophores. Ligands activating human ALK were recently identified as the ALKAL proteins (FAM150, AUG) by biochemical means. Our data show that this ligand–receptor pair functions in vivo in the neural crest of zebrafish to drive development of iridophores. Removal of Ltk or all three zebrafish ALKALs results in larvae completely lacking these cells. Using Drosophila and human cell lines, we show evolutionary conservation of this important interaction.