Protein tyrosine phosphatase receptor type O (Ptpro) regulates cerebellar formation during zebrafish development through modulating Fgf signaling.
Protein tyrosine phosphatase receptor type O (Ptpro) regulates cerebellar formation during zebrafish development through modulating Fgf signaling.
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DOI：
10.1007/s00018-013-1259-7
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发表时间：
2013-07
影响因子：
8
通讯作者：
Huang, Chang-Jen
中科院分区：
文献类型：
--
作者：
Liao, Wei-Hao;Cheng, Chia-Hsiung;Hung, Kuo-Sheng;Chiu, Wen-Ta;Chen, Gen-Der;Hwang, Pung-Pung;Hwang, Sheng-Ping L.;Kuan, Yung-Shu;Huang, Chang-Jen
由受体蛋白酪氨酸磷酸酶（RPTPs）控制的蛋白活性在蛋白酪氨酸激酶将细胞表面信号转导到细胞质中起着相当重要的作用。先前的研究表明，在果蝇、脊椎动物海马、视网膜和发育中的四肢中，几种rptp参与了神经元的产生、迁移和轴突引导。然而，作为RPTP的一种，O型蛋白酪氨酸磷酸酶（ptpro）是否参与调节脊椎动物大脑发育在很大程度上是未知的。我们分离了斑马鱼ptpro基因，发现其转录本主要在胚胎和成体中枢神经系统中表达。通过反义morpholino寡核苷酸敲除斑马鱼胚胎Ptpro，导致前脑和小脑出现明显缺陷，注射的斑马鱼幼鱼在受精后第4天死亡。我们进一步研究了ptpro在小脑发育中的功能，发现Fgf信号诱导的小脑模式因子ephrin-A5b （efnA5b）的表达减少，而Fgf信号在中脑-后脑边界区负反馈基因dusp6的表达在ptpro变异体中被显著诱导。进一步的分析表明，通过抑制Fgf信号传导，部分修复了ptpro变形体的小脑缺陷。此外，Ptpro与Fgf受体1a （Fgfr1a）发生物理相互作用，并以剂量依赖性的方式使Fgfr1a去磷酸化。因此，我们的研究结果表明，Ptpro活性是斑马鱼胚胎大脑模式所必需的。具体来说，Ptpro通过调节Fgf信号传导调节斑马鱼发育过程中的小脑形成。本文的在线版本（doi:10.1007/s00018-013-1259-7）包含补充资料，仅供授权用户使用。
Protein activities controlled by receptor protein tyrosine phosphatases (RPTPs) play comparably important roles in transducing cell surface signals into the cytoplasm by protein tyrosine kinases. Previous studies showed that several RPTPs are involved in neuronal generation, migration, and axon guidance in Drosophila, and the vertebrate hippocampus, retina, and developing limbs. However, whether the protein tyrosine phosphatase type O (ptpro), one kind of RPTP, participates in regulating vertebrate brain development is largely unknown. We isolated the zebrafish ptpro gene and found that its transcripts are primarily expressed in the embryonic and adult central nervous system. Depletion of zebrafish embryonic Ptpro by antisense morpholino oligonucleotide knockdown resulted in prominent defects in the forebrain and cerebellum, and the injected larvae died on the 4th day post-fertilization (dpf). We further investigated the function of ptpro in cerebellar development and found that the expression of ephrin-A5b (efnA5b), a Fgf signaling induced cerebellum patterning factor, was decreased while the expression of dusp6, a negative-feedback gene of Fgf signaling in the midbrain-hindbrain boundary region, was notably induced in ptpro morphants. Further analyses demonstrated that cerebellar defects of ptpro morphants were partially rescued by inhibiting Fgf signaling. Moreover, Ptpro physically interacted with the Fgf receptor 1a (Fgfr1a) and dephosphorylated Fgfr1a in a dose-dependant manner. Therefore, our findings demonstrate that Ptpro activity is required for patterning the zebrafish embryonic brain. Specifically, Ptpro regulates cerebellar formation during zebrafish development through modulating Fgf signaling. The online version of this article (doi:10.1007/s00018-013-1259-7) contains supplementary material, which is available to authorized users.
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