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.
Highlights
A universal property of animal development is the capacity to scale body size and pattern in response to environmental conditions as well as during evolution [1]
What mechanisms control the sizes of animal organs? It is known that organ growth is the product of two systems: an intrinsic system that coordinates cell proliferation with the specification of cell fate, and an extrinsic system that synchronizes growth with nutrient levels
Equivalent results were obtained in the developing head primordium: mutation of wts or ex leads to dramatic overgrowth of head tissue, which is suppressed when the head is mutant for Tor or the Insulin Receptor (InR) pathway kinase Akt (S1P–S1X Fig)
Summary
A universal property of animal development is the capacity to scale body size and pattern in response to environmental conditions as well as during evolution [1]. Drosophila species differ over ~5-fold in body size but are highly similar in shape. Animals possess distinct systems for controlling growth locally and systemically: organ-intrinsic signaling mechanisms couple growth to patterning and morphogenesis, defining organ shape and dimension [2,3,4]; humoral signals, produced on feeding, act globally to control body size [5]. Cells in developing organs must integrate local and global information and proliferate generating organs— and entire animals—that are functioning, proportional wholes [6,7,8,9]
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