The tumor suppressor PRDM5 regulates Wnt signaling at early stages of zebrafish development.
The tumor suppressor PRDM5 regulates Wnt signaling at early stages of zebrafish development.
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DOI：
10.1371/journal.pone.0004273
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Alcalay M
中科院分区：
文献类型：
--
作者：
Meani N;Pezzimenti F;Deflorian G;Mione M;Alcalay M
PRDM基因是一个转录调节因子家族，其调节细胞过程，例如分化、细胞生长和凋亡。一些家族成员参与组织或器官成熟，并在胚胎发育的特定阶段差异表达。PRDM 5是最近鉴定的家族成员，其作为转录抑制因子起作用，并且在不同类型的癌症中作为推定的肿瘤抑制因子起作用。使用基因表达谱，我们发现PRDM 5在人U2 OS细胞中的转录靶点包括参与发育过程的关键基因，特别是调节wnt信号传导的关键基因。因此，我们通过在斑马鱼胚胎中进行功能丧失和功能获得实验来评估PRDM 5的体内功能。prdm 5的缺失导致原肠胚形成期间形态发生运动受损，并增加axin+/−胚胎中masterblind表型的发生，其特征在于眼睛和端脑的丧失。PRDM 5 mRNA的过表达对前部神经结构的发育有相反的影响，并导致胚胎由于后部截断而具有较短的体轴、较大的头部和异常的体节。原位杂交实验旨在分析原肠胚形成过程中在前索板水平上wnt通路的完整性，结果显示在过度表达PRDM 5的胚胎中抑制了非典型PCP wnt信号传导，在缺乏Prdm 5的胚胎中过度激活了wnt/β-连环蛋白信号传导。我们的数据表明，PRDM 5调节经典和非经典wnt途径的组分的表达，并在体内负调节wnt信号传导。
PRDM genes are a family of transcriptional regulators that modulate cellular processes such as differentiation, cell growth and apoptosis. Some family members are involved in tissue or organ maturation, and are differentially expressed in specific phases of embryonic development. PRDM5 is a recently identified family member that functions as a transcriptional repressor and behaves as a putative tumor suppressor in different types of cancer. Using gene expression profiling, we found that transcriptional targets of PRDM5 in human U2OS cells include critical genes involved in developmental processes, and specifically in regulating wnt signaling. We therefore assessed PRDM5 function in vivo by performing loss-of-function and gain-of-function experiments in zebrafish embryos. Depletion of prdm5 resulted in impairment of morphogenetic movements during gastrulation and increased the occurrence of the masterblind phenotype in axin+/− embryos, characterized by the loss of eyes and telencephalon. Overexpression of PRDM5 mRNA had opposite effects on the development of anterior neural structures, and resulted in embryos with a shorter body axis due to posterior truncation, a bigger head and abnormal somites. In situ hybridization experiments aimed at analyzing the integrity of wnt pathways during gastrulation at the level of the prechordal plate revealed inhibition of non canonical PCP wnt signaling in embryos overexpressing PRDM5, and over-activation of wnt/β-catenin signaling in embryos lacking Prdm5. Our data demonstrate that PRDM5 regulates the expression of components of both canonical and non canonical wnt pathways and negatively modulates wnt signaling in vivo.
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