Neuroblast differentiation during development and in neuroblastoma requires KIF1B beta-mediated transport of TRKA

摘要

We recently identified pathogenic KIF1B beta mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted KIF1B beta in the mouse sympathetic nervous system and observed impaired sympathetic nervous function and misexpression of genes required for sympathoadrenal lineage differentiation. We discovered that KIF1B beta is required for nerve growth factor (NGF)-dependent neuronal differentiation through anterograde transport of the NGF receptor TRKA. Moreover, pathogenic KIF1B beta mutations identified in neuroblastoma impair TRKA transport. Expression of neuronal differentiation markers is ablated in both KIF1B beta-deficient mouse neuroblasts and human neuroblastomas that lack KIF1B beta. Transcriptomic analyses show that unfavorable neuroblastomas resemble mouse sympathetic neuroblasts lacking KIF1B beta independent of MYCN amplification and the loss of genes neighboring KIF1B on chromosome 1p36. Thus, defective precursor cell differentiation, a common trait of aggressive childhood malignancies, is a pathogenic effect of KIF1B beta loss in neuroblastomas. Furthermore, neuropathy-associated KIF1B beta mutations impede cargo transport, providing a direct link between neuroblastomas and neurodegeneration.