RORα coordinates reciprocal signaling in cerebellar development through Sonic hedgehog and calcium-dependent pathways
RORα coordinates reciprocal signaling in cerebellar development through Sonic hedgehog and calcium-dependent pathways
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DOI：
10.1016/s0896-6273(03)00769-4
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发表时间：
2003-12-18
期刊：
影响因子：
16.2
通讯作者：
Hamilton, BA
中科院分区：
文献类型：
--
作者：
Gold, DA;Baek, SH;Hamilton, BA
小脑为理解传入神经元和靶神经元如何在发育过程中协调连续的细胞间信号和细胞自主遗传程序提供了一个很好的系统。孤儿核受体RORpha的突变阻止了浦肯野细胞的分化，继而失去了传入颗粒细胞。我们发现，RORpha的早期转录靶点既包括传入祖细胞的有丝分裂信号，也包括处理其后续突触输入所需的信号转导基因。RORpha通过招募基因特定的转录辅助因子集发挥作用，包括β-连环蛋白、p300和Tip60，但似乎独立于CBP。一个目标启动子是Sonic Hedgehog，重组Sonic Hedgehog可以恢复RORpha缺陷小脑中颗粒前体的增殖。我们的结果提示了RORpha和β-连环蛋白通路之间的联系，证实了核受体在不同的靶基因上使用不同的辅助激活复合体，并为RORpha在协调小脑发育中相互信号所需的基因表达方面的早期表达提供了逻辑。
The cerebellum provides an excellent system for understanding how afferent and target neurons coordinate sequential intercellular signals and cell-autonomous genetic programs in development. Mutations in the orphan nuclear receptor RORalpha block Purkinje cell differentiation with a secondary loss of afferent granule cells. We show that early transcriptional targets of RORalpha include both mitogenic signals for afferent progenitors and signal transduction genes required to process their subsequent synaptic input. RORalpha acts through recruitment of gene-specific sets of transcriptional cofactors, including beta-catenin, p300, and Tip60, but appears independent of CBP. One target promoter is Sonic hedgehog, and recombinant Sonic hedgehog restores granule precursor proliferation in RORalpha-deficient cerebellum. Our results suggest a link between RORalpha and beta-catenin pathways, confirm that a nuclear receptor employs distinct coactivator complexes at different target genes, and provide a logic for early RORalpha expression in coordinating expression of genes required for reciprocal signals in cerebellar development.