The Stress-Response Gene redd1 Regulates Dorsoventral Patterning by Antagonizing Wnt/β-catenin Activity in Zebrafish

REDD1/redd1 is a stress-response gene that is induced under various stressful conditions such as hypoxia, DNA damage, and energy stress. The increased REDD1 inhibits mTOR signaling and cell growth. Here we report an unexpected role of Redd1 in regulating dorsoventral patterning in zebrafish embryos and the underlying mechanisms. Zebrafish redd1 mRNA is maternally deposited. Although it is ubiquitously detected in many adult tissues, its expression is highly tissue-specific and dynamic during early development. Hypoxia and heat shock strongly induce redd1 expression in zebrafish embryos. Knockdown of Redd1 using two independent morpholinos results in dorsalized embryos and this effect can be rescued by injecting redd1 mRNA. Forced expression of Redd1 ventralizes embryos. Co-expression of Redd1 with Wnt3a or a constitutively active form of β-catenin suggests that Redd1 alters dorsoventral patterning by antagonizing the Wnt/β-catenin signaling pathway. These findings have unraveled a novel role of Redd1 in early development by antagonizing Wnt/β-catenin signaling.

REDD1（redd1）是一种应激反应基因，可在缺氧、DNA损伤及能量应激等多种应激条件下被诱导表达。其表达升高后会抑制mTOR信号通路与细胞生长。本研究报道了Redd1在斑马鱼胚胎背腹模式建成调控中的非预期功能及其潜在分子机制。斑马鱼redd1 mRNA为母源沉积型。尽管该基因在多种成年组织中广泛表达，但在早期发育过程中其表达呈现高度的组织特异性与动态变化特征。缺氧与热激可强烈诱导斑马鱼胚胎中redd1的表达。使用两种独立的吗啉代寡核苷酸敲低Redd1会导致胚胎背化，该表型可通过注射redd1 mRNA得以挽救。过表达Redd1则可使胚胎腹化。将Redd1与Wnt3a或组成型激活型β-连环蛋白共表达的实验结果表明，Redd1通过拮抗Wnt/β-连环蛋白信号通路来调控背腹模式建成。本研究发现阐明了Redd1通过拮抗Wnt/β-连环蛋白信号通路在早期发育中发挥的全新功能。