Ingaramo, M. C. | Search bioRxiv

bioRxiv2023

Myc-regulated miRNAs modulate p53 expression and impact animal survival under nutrient deprivation

The conserved transcription factor Myc regulates cell growth, proliferation and apoptosis, and its deregulation has been associated with human pathologies. Although specific miRNAs have been identified as fundamental components of the Myc tumorigenic program, how Myc regulates miRNA biogenesis remains controversial. Here we showed that Myc functions as an important regulator of miRNA biogenesis in Drosophila by influencing both miRNA gene expression and processing. Through the analysis of ChIP-Seq datasets, we discovered that nearly 56% of Drosophila miRNA genes show dMyc binding, exhibiting either the canonical or non-canonical E-box sequences within the peak region. Consistently, reduction of dMyc levels resulted in widespread downregulation of miRNAs gene expression. dMyc also modulates miRNA processing and activity by controlling Drosha and AGO1 levels through direct transcriptional regulation. By using in vivo miRNA activity sensors we demonstrated that dMyc promotes miRNA-mediated silencing in different tissues, including the wing primordium and the fat body. We also showed that dMyc-dependent expression of miR-305 in the fat body modulates Dmp53 levels depending on nutrient availability, having a profound impact on the ability of the organism to respond to nutrient stress. Indeed, dMyc depletion in the fat body resulted in extended survival to nutrient deprivation which was reverted by expression of either miR-305 or a dominant negative version of Dmp53. Our study reveals a previously unrecognized function of dMyc as an important regulator of miRNA biogenesis and suggests that Myc-dependent expression of specific miRNAs may have important tissue-specific functions.

developmental biology↗

bioRxiv2019

Eiger/TNFα-mediated Dilp8 and ROS production coordinate intra-organ growth in Drosophila

Coordinated intra- and inter-organ growth is essential during animal development to generate individuals of proper size and shape. The Drosophila wing has been a valuable model system to reveal the existence of a stress response mechanism mediated by Drosophila p53 (Dmp53) and involved in the coordination of tissue growth between adjacent cell populations upon targeted reduction of growth rates. Here we present evidence that a two-step molecular mechanism is being used by Dmp53 to reduce in a non-autonomous manner growth and proliferation in adjacent cell populations. First, Dmp53-mediated transcriptional induction of Drosophila TNF ligand Eiger leads to cell autonomous activation of JNK. Second, two different signaling events downstream of the Eiger/JNK axis are induced in the growth depleted territory in order to independently regulate tissue size and cell number in adjacent cell populations. Whereas expression of the systemic hormone dILP8 coordinates intra-organ growth and final tissue size, induction of Reactive Oxygen Species downstream of Eiger/JNK and, as a consequence of apoptosis induction, acts non-cell-autonomously to regulate proliferation rates of adjacent epithelial cells. Our results unravel how local and systemic signals can act concertedly to coordinate growth and proliferation within an organ in order to generate well-proportioned organs and functionally integrated adults.\n\nAuthor SummaryCoordination of growth between the different parts of a given developing organ is an absolute requirement for the generation of functionally integrated structures during animal development. Although this question has fascinated biologists for centuries, the responsible molecular mechanisms have remained so far unknown. In this work, we have used the developing wing primordium of Drosophila to identify the molecular mechanisms and signaling molecules mediating communication between adjacent cell populations upon targeted reduction in growth rates. We first present evidence that activation of Drosophila p53 in the growth-depleted territory induces expression of the fly TNF ligand Eiger which cell autonomously activates the JNK stress signaling pathway. While JNK-dependent expression of the systemic hormone dILP8 reduces growth and final size of the adjacent territories, production of Reactive Oxygen Species downstream of JNK and the apoptotic machinery act locally to regulate proliferation rates in adjacent epithelial cells. Our data reveal how signals acting locally or systemically can regulate cell proliferation and growth independently to accomplish coordination in tissue size and cell number among different parts of an organ in order to give rise to well-proportioned adult structures.\n\nHIGHLIGHTS{checkmark} Dmp53-dependent Eiger expression is required to coordinate intra-organ growth\n{checkmark}Eiger acts through its receptor Grindelwald and JNK signaling to reduce growth and proliferation rates in a non-cell-autonomous manner\n{checkmark}Eiger/JNK-dependent Dilp8 expression coordinates intra-organ growth but not proliferation\n{checkmark}Eiger/JNK activation triggers ROS production\n{checkmark}ROS act non-cell-autonomously to regulate proliferation of adjacent epithelial cells.

developmental biology↗