Scaling the Drosophila Wing: TOR-Dependent Target Gene Access by the Hippo Pathway Transducer Yorkie

Abstract

Organ growth is controlled by patterning signals that operate locally (e.g., Wingless/Ints [Wnts], Bone Morphogenetic Proteins [BMPs], and Hedgehogs [Hhs]) and scaled by nutrient-dependent signals that act systemically (e.g., Insulin-like peptides [ILPs] transduced by the Target of Rapamycin [TOR] pathway). How cells integrate these distinct inputs to generate organs of the appropriate size and shape is largely unknown. The transcriptional coactivator Yorkie (Yki, a YES-Associated Protein, or YAP) acts downstream of patterning morphogens and other tissue-intrinsic signals to promote organ growth. Yki activity is regulated primarily by the Warts/Hippo (Wts/Hpo) tumour suppressor pathway, which impedes nuclear access of Yki by a cytoplasmic tethering mechanism. Here, we show that the TOR pathway regulates Yki by a separate and novel mechanism in the Drosophila wing. Instead of controlling Yki nuclear access, TOR signaling governs Yki action after it reaches the nucleus by allowing it to gain access to its target genes. When TOR activity is inhibited, Yki accumulates in the nucleus but is sequestered from its normal growth-promoting target genes—a phenomenon we term “nuclear seclusion.” Hence, we posit that in addition to its well-known role in stimulating cellular metabolism in response to nutrients, TOR also promotes wing growth by liberating Yki from nuclear seclusion, a parallel pathway that we propose contributes to the scaling of wing size with nutrient availability.

YAP and TAZ in epithelial stem cells: A sensor for cell polarity, mechanical forces and tissue damage

“…Results in Drosophila support the notion that PI3K signalling can activate Yorkie . There is also a requirement for minimal TOR activation to maintain Yorkie activity in Drosophila . In mice, there is a good correlation between EGF ligand and receptor expression and YAP/TAZ nuclear localisation in skin , and EGF ligands such as amphiregulin (AREG) are also transcriptional targets of YAP/TAZ in several tissues, forming a possible positive feedback loop in vivo .…”

Electron transport chain biogenesis activated by a JNK-insulin-Myc relay primes mitochondrial inheritance inDrosophila

“…These data support a critical role of IIS in ETC biogenesis and mtDNA replication. Intriguingly, the activity of IIS, revealed by staining for phosphorylated AKT (p-AKT) (Parker and Struhl, 2015), was also increased in the germarium region 2B and maintained until mid-stage egg chambers (Fig 3D and S3A), a pattern similar to that of Myc protein. In contrast, total AKT staining was uniform in the germarium (Fig 3D).…”

Mechanisms of Hippo pathway regulation

“…It is worth noting that mTORC1 is highly sensitive to nutrient availability and cellular energy status. In Drosophila, the Tor pathway can regulate Yki's ability to access its target genes in the nucleus (Parker and Struhl 2015). Tor inhibition by nutrient deprivation prevents nuclear Yki from activating its target genes.…”