Abstract
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.
Highlights
The Wnt/b-catenin signaling pathway, known as the canonical Wnt signaling pathway, plays a pivotal role in embryogenesis and in adult tissue homeostasis [1,2,3]
By searching public databases and performing 59- and 39- rapid amplification of complementary DNA (cDNA) ends (RACE) experiments, we identified and cloned zebrafish redd1 gene (GenBank accession number: HM114348)
Recent studies in human REDD1 revealed that REDD1 undergoes GSK3bdependent phosphorylation through Thr23 and Thr25, and this leads to its degradation [32]
Summary
The Wnt/b-catenin signaling pathway, known as the canonical Wnt signaling pathway, plays a pivotal role in embryogenesis and in adult tissue homeostasis [1,2,3]. Aberrant regulation of the Wnt/b-catenin pathway is associated with many human diseases, such as cancer, osteoporosis, aging, and degenerative disorders [2,4]. The transcriptional co-activator bcatenin is a key regulation step in this pathway. In the absence of Wnt ligands, cytoplasmic b-catenin is phosphorylated by the ‘‘destruction complex’’ consisting of Axin, APC, CK1 and GSK3b, resulting in b-catenin recognition by b-Trcp and subsequent degradation [5]. When Wnt ligands bind to the receptors Frizzled and co-receptor low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6), the Axin complex is recruited to the receptors and b-catenin phosphorylation and degradation are inhibited [5]. The stabilized b-catenin accumulates and translocates into the nucleus to form complexes with the transcription factors TCF/LEF and activates target gene expression
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