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Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA.
- 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.)
- Subjects :
- Animals
Apoptosis genetics
Cell Line, Tumor
Gene Expression Regulation, Developmental
Gene Silencing
Mutation
Neuroblastoma physiopathology
Neurodegenerative Diseases genetics
Neurodegenerative Diseases physiopathology
Neurofibromin 1 genetics
Neurofibromin 1 metabolism
PC12 Cells
Rats
Signal Transduction genetics
Sympathetic Nervous System cytology
ras Proteins genetics
Cell Differentiation genetics
Kinesins genetics
Kinesins metabolism
Neuroblastoma genetics
Neurons cytology
Receptor, trkA metabolism
Subjects
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