Leukocyte receptor tyrosine kinase interacts with secreted midkine to promote survival of migrating neural crest cells

Neural crest cells migrate long distances throughout the embryo and rely on extracellular signals that attract, repel and/or stimulate survival to ensure proper contribution to target derivatives. Here, we show that leukocyte receptor tyrosine kinase (LTK), an ALK-type receptor tyrosine kinase, is expressed by neural crest cells during early migratory stages in chicken embryos. Loss of LTK in the cranial neural crest impairs migration and results in increased levels of apoptosis. Conversely, midkine, previously proposed as a ligand for ALK, is secreted by the non-neural ectoderm during early neural crest migratory stages and internalized by neural crest cells in vivo. Similar to loss of LTK, loss of midkine reduces survival of the migratory neural crest. Moreover, we show by proximity ligation and co-immunoprecipitation assays that midkine binds to LTK. Taken together, these results suggest that LTK in neural crest cells interacts with midkine emanating from the non-neural ectoderm to promote cell survival, revealing a new signaling pathway that is essential for neural crest development.