Leukocyte Tyrosine Kinase (Ltk) Is the Mendelian Determinant of the Axolotl Melanoid Color Variant

Abstract

The great diversity of color patterns observed among amphibians is largely explained by the differentiation of relatively few pigment cell types during development. Mexican axolotls present a variety of color phenotypes that span the continuum from leucistic to highly melanistic. The melanoid axolotl is a Mendelian variant characterized by large numbers of melanophores, proportionally fewer xanthophores, and no iridophores. Early studies of melanoid were influential in developing the single-origin hypothesis of pigment cell development, wherein it has been proposed that all three pigment cell types derive from a common progenitor cell, with pigment metabolites playing potential roles in directing the development of organelles that define different pigment cell types. Specifically, these studies identified xanthine dehydrogenase (XDH) activity as a mechanism for the permissive differentiation of melanophores at the expense of xanthophores and iridophores. We used bulked segregant RNA-Seq to screen the axolotl genome for melanoid candidate genes and identify the associated locus. Dissimilar frequencies of single-nucleotide polymorphisms were identified between pooled RNA samples of wild-type and melanoid siblings for a region on chromosome 14q. This region contains gephyrin (Gphn), an enzyme that catalyzes the synthesis of the molybdenum cofactor that is required for XDH activity, and leukocyte tyrosine kinase (Ltk), a cell surface signaling receptor that is required for iridophore differentiation in zebrafish. Wild-type Ltk crispants present similar pigment phenotypes to melanoid, strongly implicating Ltk as the melanoid locus. In concert with recent findings in zebrafish, our results support the idea of direct fate specification of pigment cells and, more generally, the single-origin hypothesis of pigment cell development.

The dynamic behavior of chromatophores marks the transition from bands to spots in leopard geckos

“…S15 B ), required for the development of iridophores in zebrafish ( 49 ). Such functional diversification of coloration genes has been previously reported; for example in axolotl, Ltk mutants lack all iridophores and have fewer xanthophores ( 50 ).…”

Multifaceted Roles of ALK Family Receptors and Augmentor Ligands in Health and Disease: A Comprehensive Review

“…Humans lack iridophores, but melanocytes that induce coloration arise from the neural crest [106]. Recently, LTK expression was linked to the melanoid color variant of amphibian axolotls [107]. In an animal model of uveal melanoma, ALK was found to be positive in all samples, and crizotinib prevented their metastasis [108,109].…”