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Alk signaling in sympathetic neurogenesis and neuroblastoma predisposition

      Neuroblastoma (NB) is a childhood tumor that arises from developing sympathetic ganglia and adrenal medulla. The restriction of NB to sympathoadrenal tissues is explained by unique traits of sympathetic neuron and chromaffin cell generation involving proliferation of already differentiated neuroblasts. Activating mutations in the anaplastic lymphoma kinase (ALK) gene have been identified in both sporadic and familial forms of NB. Here, we focus on the normal function of Alk signaling in the control of sympathetic neurogenesis as well as on effects of mutant Alk. Using loss-of-function approaches in the chick embryo we demonstrate that Alk signaling is essential for sympathetic neurogenesis. Forced expression of Alk and constitutively-active Alk mutants increase proliferation of cultured sympathetic neuroblasts. Alk activation by the ligand Midkine stimulates neuroblast proliferation and results in enlarged sympathetic ganglia in the chick embryo. These results demonstrate that neuroblast proliferation in sympathetic ganglia is controlled by Alk signaling and that NB predisposition by activating Alk mutations may be explained by effects on the extent and timing of neurogenesis.
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