Abstract
A fundamental question of biology is what determines organ size. Despite demonstrations that factors within organs determine their sizes, intrinsic size control mechanisms remain elusive. Here we show that Drosophila wing size is regulated by JNK signaling during development. JNK is active in a stripe along the center of developing wings, and modulating JNK signaling within this stripe changes organ size. This JNK stripe influences proliferation in a non-canonical, Jun-independent manner by inhibiting the Hippo pathway. Localized JNK activity is established by Hedgehog signaling, where Ci elevates dTRAF1 expression. As the dTRAF1 homolog, TRAF4, is amplified in numerous cancers, these findings provide a new mechanism for how the Hedgehog pathway could contribute to tumorigenesis, and, more importantly, provides a new strategy for cancer therapies. Finally, modulation of JNK signaling centers in developing antennae and legs changes their sizes, suggesting a more generalizable role for JNK signaling in developmental organ size control.
Highlights
Within a species, organ size is remarkably reproducible
Developing Drosophila wings transplanted into adult abdomens grow to the proper size, indicating that the information determining size is located within the developing organ (Garcıa-Bellido, 1965)
Jun N-terminal Kinase (JNK) is active in the developing Drosophila wing pouch
Summary
Organ size is remarkably reproducible. While extrinsic factors like hormones are required for growth, classic transplantation experiments indicate that intrinsic factors within organs determine size (Bryant and Simpson, 1984). The molecular mechanisms underlying intrinsic organ size control remain unclear (Vogel, 2013) While morphogens direct both patterning and growth of developing organs (Tabata and Takei, 2004), a Willsey et al eLife 2016;5:e11491. The role of JNK in activating Yorkie signaling and growth during regeneration and tumorigenesis is clear (Enomoto and Igaki, 2012; Sun and Irvine, 2011; Sun and Irvine 2013), it is not known to regulate proliferation and growth during developmental size control. We show that localized JNK activity in the developing wing is established by Hedgehog (Hh) signaling and controls wing size through a non-canonical, Jun-independent signaling mechanism that inhibits the Hippo pathway
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