Fell Stuart M, Li Shuijie, Wallis Karin, Kock Anna, Surova Olga, Rraklli Vilma, Höfig Carolin S, Li Wenyu, Mittag Jens, Henriksson Marie Arsenian, Kenchappa Rajappa S, Holmberg Johan, Kogner Per, Schlisio Susanne
Ludwig Institute for Cancer Research Ltd., SE-17177 Stockholm, Sweden.
Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden.
Genes Dev. 2017 May 15;31(10):1036-1053. doi: 10.1101/gad.297077.117.
We recently identified pathogenic β mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted 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 β mutations identified in neuroblastoma impair TRKA transport. Expression of neuronal differentiation markers is ablated in both β-deficient mouse neuroblasts and human neuroblastomas that lack KIF1Bβ. Transcriptomic analyses show that unfavorable neuroblastomas resemble mouse sympathetic neuroblasts lacking KIF1Bβ independent of amplification and the loss of genes neighboring 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 mutations impede cargo transport, providing a direct link between neuroblastomas and neurodegeneration.
我们最近在发育性凋亡存在缺陷的交感神经系统恶性肿瘤中鉴定出致病性β突变。在此，我们在小鼠交感神经系统中删除了β，观察到交感神经功能受损以及交感肾上腺谱系分化所需基因的错误表达。我们发现，KIF1Bβ通过神经生长因子（NGF）受体TRKA的顺向转运，对于NGF依赖性神经元分化是必需的。此外，在神经母细胞瘤中鉴定出的致病性β突变会损害TRKA转运。在缺乏KIF1Bβ的β缺陷小鼠神经母细胞和人类神经母细胞瘤中，神经元分化标志物的表达均被消除。转录组分析表明，不良神经母细胞瘤类似于缺乏KIF1Bβ的小鼠交感神经母细胞，与1p36染色体上基因的扩增和缺失无关。因此，前驱细胞分化缺陷是侵袭性儿童恶性肿瘤的一个共同特征，是神经母细胞瘤中KIF1Bβ缺失的致病效应。此外，与神经病变相关的突变会阻碍货物运输，在神经母细胞瘤和神经退行性变之间建立了直接联系。
