Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA

Stuart M. Fell, Shuijie Li, Karin Wallis, Anna Kock, Olga Surova, Vilma Rraklli, Carolin S. Höfig, Wenyu Li, Jens Mittag, Marie Arsenian Henriksson, Rajappa S. Kenchappa, Johan Holmberg, Per Kogner, Susanne Schlisio

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

We recently identified pathogenic KIF1Bβ mutations in sympathetic nervous systemmalignancies that are defective in developmental apoptosis. Here we deleted KIF1Bβ in the mouse sympathetic nervous system and observed impaired sympathetic nervous function and misexpression of genes required for sympathoadrenal lineage differentiation. We discovered that KIF1Bβ is required for nerve growth factor (NGF)-dependent neuronal differentiation through anterograde transport of the NGF receptor TRKA. Moreover, pathogenic KIF1Bβ mutations identified in neuroblastoma impair TRKA transport. Expression of neuronal differentiation markers is ablated in both KIF1Bβ-deficient mouse neuroblasts and human neuroblastomas that lack KIF1Bβ. Transcriptomic analyses show that unfavorable neuroblastomas resemble mouse sympathetic neuroblasts lacking KIF1Bβ 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 KIF1Bβ loss in neuroblastomas. Furthermore, neuropathy-associated KIF1Bβ mutations impede cargo transport, providing a direct link between neuroblastomas and neurodegeneration.

Original languageEnglish (US)
Pages (from-to)1036-1053
Number of pages18
JournalGenes and Development
Volume31
Issue number10
DOIs
StatePublished - May 15 2017

Keywords

  • Chromosome 1p36 loss
  • KIF1Bβ
  • NGF
  • Neuroblast differentiation
  • Neuroblastoma
  • TRKA

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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