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

Authors :
Fell SM
Li S
Wallis K
Kock A
Surova O
Rraklli V
Höfig CS
Li W
Mittag J
Henriksson MA
Kenchappa RS
Holmberg J
Kogner P
Schlisio S
Source :
Genes & development [Genes Dev] 2017 May 15; Vol. 31 (10), pp. 1036-1053.
Publication Year :
2017

Abstract

We recently identified pathogenic KIF1B β mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted KIF1B β 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 KIF1B β mutations identified in neuroblastoma impair TRKA transport. Expression of neuronal differentiation markers is ablated in both KIF1B β-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.<br /> (© 2017 Fell et al.; Published by Cold Spring Harbor Laboratory Press.)

Details

Language :
English
ISSN :
1549-5477
Volume :
31
Issue :
10
Database :
MEDLINE
Journal :
Genes & development
Publication Type :
Academic Journal
Accession number :
28637693
Full Text :
https://doi.org/10.1101/gad.297077.117