Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.

Adviser: Joseph Schlessinger.

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Receptor tyrosine kinases (RTK) and their stimulatory ligands regulate a variety of cellular processes. Many diseases, including several cancers, are driven by mutations in or dysregulation of RTKs and their signaling pathways. Alk and Ltk were identified as "orphan" RTKs with oncogenic potential. Recently, ALKALI and ALKAL2 (also named Augmentor-beta and alpha or, FAM150A and B, respectively) were discovered as physiological ligands of Alk and Ltk. In this dissertation work, we investigate the evolution of these augmentor ligands and use the zebrafish model organism to explore the physiological function and in vivo links between Alk, Ltk, and the Augmentors. We demonstrate that augmentors are unique to vertebrates and that particular Augmentors activate Ltk in a tissue-specific context to induce iridophore differentiation from neural crest-derived cells and pigment progenitor cells.

Unlike the two ligands encoded by mammalian genomes, the zebrafish genome contains three ligands; aug-alpha1, aug-alpha2, and aug-beta. Augmentor deficiency results in strong impairment in iridophore patterning of embryonic and adult zebrafish that is phenocopied in Ltk-deficient fish. We demonstrate that aug-alpha1 and aug-alpha 2 are essential for embryonic iridophore development and adult body coloration. In contrast, aug-alpha2 and aug-beta are necessary for iridophore formation in the adult eye. Importantly, these processes are entirely mediated by Ltk and not by Alk.

Analysis of the Ltk primary sequence revealed that zebrafish Ltk is more similar to human ALK than to human LTK. Therefore, we propose that zebrafish contain two orthologues of ALK-like RTKs, alk-1 and alk-2 rather than the so-called zebrafish "Ltk" and "Alk." However, for the purpose of clarity, I will continue to use the designation Ltk throughout this thesis.

These experiments establish an in vivo link between Augmentor ligands and Ltk. We demonstrate that these hormone-like molecules are critical factors influencing neural crest cell differentiation and progenitor/stem cell fates in zebrafish, suggesting a role for Augmentors in control of similar processes in higher organisms.