TGFβ/Activin signalling is required for ribosome biogenesis and cell growth inDrosophilasalivary glands

Abstract

Signalling by TGFβ superfamily factors plays an important role in tissue growth and cell proliferation. In Drosophila, the activity of the TGFβ/Activin signalling branch has been linked to the regulation of cell growth and proliferation, but the cellular and molecular basis for these functions are not fully understood. In this study, we show that both the RII receptor Punt (Put) and the R-Smad Smad2 are strongly required for cell and tissue growth. Knocking down the expression of Put or Smad2 in salivary glands causes alterations in nucleolar structure and functions. Cells with decreased TGFβ/Activin signalling accumulate intermediate pre-rRNA transcripts containing internal transcribed spacer 1 regions accompanied by the nucleolar retention of ribosomal proteins. Thus, our results show that TGFβ/Activin signalling is required for ribosomal biogenesis, a key aspect of cellular growth control. Importantly, overexpression of Put enhanced cell growth induced by Drosophila Myc, a well-characterized inducer of nucleolar hypertrophy and ribosome biogenesis.

An eye-targeted double-RNAi screen reveals negative roles for the Archipelago ubiquitin ligase and CtBP inDrosophilaDpp-BMP2/4 signaling

“…Eye-targeted knockdown of the type-II receptor punt using ey-Gal4 driven expression of UAS- punt RNAi causes absence or very strong reduction of adult retinal tissue in the majority of animals (Figure 1; (Marinho et al, 2013; Martins et al, 2017). Additionally, 42% of ey> punt RNAi animals die during pupal stage.…”

“…We observed that rescue of punt RNAi eye phenotype by ago RNAi indeed correlated with increased Myc protein expression (Figure S4). Next, we tested the hypothesis that knockdown of ago rescues Dpp BMP2-4 signaling through the detected Myc upregulation, given the previously described genetic interaction between overexpression of Myc and Punt in eye growth and differentiation (Martins et al, 2017). Indeed that was the case, as overexpression of Myc was also sufficient for a partial rescue of differentiation in all the eye discs and adults that we observed (Figure 3B, 3F, 3I).…”

“…This supports the hypothesis that the mechanism for their genetic interaction with Punt that we identified in this study includes the contribution of Myc upregulation and tissue growth. We have also recently demonstrated that overexpression of Myc and Punt is able to enhance tissue growth and retinal differentiation in the eye disc (Martins et al, 2017). In here, we also show that other growth-stimulating conditions like overexpression of CycE or CycD-Cdk4 (Datar et al, 2000a) can partially rescue Punt knockdown.…”

“…Vito is a transcriptional target of Myc and encodes an 5’ RNA exonuclease regulating rRNA and ribosome biogenesis in the nucleolus (Marinho et al, 2011). The second branch of the TGFβ signaling superfamily, the TGFβ/Activin pathway, has also been shown to be required for cell growth in the salivary glands through the control of ribosome biogenesis (Martins et al, 2017).…”

NOL12 Repression Induces Nucleolar Stress-Driven Cellular Senescence and Is Associated with Normative Aging

“…Furthermore, through a retina-targeted double RNA interference (RNAi) screen, we identified a genetic interaction between viriato and several Drosophila transforming growth factor ␤ (TGF-␤) signaling gene members (22). This led us to study and implicate TGF-␤/activin signaling in the regulation of nucleolar biogenesis and cell growth in Drosophila salivary glands (23). Furthermore, we also disclosed that, during retina development, viriato knockdown induced an increase of p53-independent, caspase-mediated apoptotic cell death (16).…”