Discoidin domain receptor 1 functions in axon extension of cerebellar granule neurons
Discoidin domain receptor 1 functions in axon extension of cerebellar granule neurons
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DOI：
10.1101/gad.821600
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发表时间：
2000-09-01
影响因子：
10.5
通讯作者：
Hatten, ME
中科院分区：
文献类型：
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作者：
Bhatt, RS;Tomoda, T;Hatten, ME
在发育中的小脑中，颗粒神经元轴突生长是与小脑的主要输出神经元浦肯野神经元建立适当连接的关键步骤。在寻找在这一过程中发挥作用的基因的过程中，我们确定了一个受体酪氨酸激酶盘状结构域受体1（DDR 1）在颗粒细胞的整个发展过程中表达。DDR 1在未成熟颗粒细胞中的显性负性形式的过度表达导致神经突生长在体外、在分离的原代培养物中以及在新生儿小脑的器官型切片中的体内严重减少。未能延伸轴突的颗粒细胞对分化标志物如TAG-1和神经元特异性III类p-微管蛋白呈阳性，表明颗粒细胞致力于终末分化后发育受到影响。DDR 1激活似乎是由其配体胶原介导的，胶原定位于发育中小脑的软脑膜层，从而导致颗粒细胞平行纤维延伸。因此，我们的研究结果表明，胶原蛋白-DDR 1信号是必不可少的颗粒神经元轴突的形成，并进一步表明一个独特的作用，小脑皮质组织发生的软脑膜。
In the developing cerebellum, granule neuron axon outgrowth is a key step toward establishing proper connections with Purkinje neurons, the principal output neuron of the cerebellum. During a search for genes that function in this process, we identified a receptor tyrosine kinase discoidin domain receptor 1 (DDR1) expressed in granule cells throughout their development. Overexpression of a dominant-negative form of DDR1 in immature granule cells results in severe reduction of neurite outgrowth in vitro, in dissociated primary culture, and in vivo, in organotypic slices of neonatal cerebellum. Granule cells that fail to extend axons are positive for differentiation markers such as TAG-1 and the neuron-specific class III p-tubulin, suggesting that development is affected after granule cells commit to terminal differentiation. DDR1 activation appears to be mediated by its ligand, collagen, which is localized to the pial layer of the developing cerebellum, thereby leading to granule cell parallel fiber extension. Our results therefore indicate that collagen-DDR1 signaling is essential for granule neuron axon formation and further suggest a unique role of pia in cerebellar cortex histogenesis.