Abstract
Both Hippo signaling pathways and cell polarity regulation are critical for cell proliferation and the maintenance of tissue homeostasis, despite the well-established connections between cell polarity disruption and Hippo inactivation, the molecular mechanism by which aberrant cell polarity induces Hippo-mediated overgrowth remains underexplored. Here we use Drosophila wing discs as a model and identify the Wnd-Nmo axis as an important molecular link that bridges loss-of-cell polarity-triggered Hippo inactivation and overgrowth. We show that Wallenda (Wnd), a MAPKKK (mitogen-activated protein kinase kinase kinase) family member, is a novel regulator of Hippo pathways in Drosophila and that overexpression of Wnd promotes growth via Nemo (Nmo)- mediated Hippo pathway inactivation. We further demonstrate that both Wnd and Nmo are required for loss-of-cell polarity-induced overgrowth and Hippo inactivation. In summary, our findings provide a novel insight on how cell polarity loss contributes to overgrowth and uncover the Wnd-Nmo axis as an essential additional branch that regulates Hippo pathways in Drosophila.
Highlights
Proper control of cell proliferation is fundamental for correct organ development, disruption of which would cause tumorigenesis
Given that ectopic wnd expression can induce the up-regulation of wingless and Cyclin E (cycE) (Ma et al, 2016), two known downstream target genes of the Hippo pathway, we tested the possibility that wnd could regulate the Hippo pathway in Drosophila
We examined the transcriptional change of two additional Hippo signaling reporters, ban and ex (Cho et al, 2006; Thompson and Cohen, 2006), and found that upon Wnd overexpression under ptc promoter along the anterior-posterior boundary of wing imaginal discs, an obvious up-regulation of ban-lacZ was seen (Figures 1F,F ), compared with the wild-type control (Figures 1E,E )
Summary
Proper control of cell proliferation is fundamental for correct organ development, disruption of which would cause tumorigenesis. Upon phosphorylation by Hpo, Wts is activated and subsequently phosphorylates Yki to restrict its nuclear entrance, thereby preventing the transcription of pro-proliferative target genes, including expanded (ex), bantam (ban), and Cyclin E (cycE) (Pan, 2010; Snigdha et al, 2019; Zheng and Pan, 2019) Recent advances on this evolutionary conserved pathway have revealed comprehensive roles of Hippo signaling in regulating a wide range of biological functions, ranging from cell adhesion and mechanical tension to regeneration and immune surveillance (Fallahi et al, 2016; Chen, 2019; Ma et al, 2019; Zheng and Pan, 2019).
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