Editors' ChoiceDevelopmental Biology

Yorkie Feedback Goes Both Ways

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Sci. Signal.  15 Oct 2013:
Vol. 6, Issue 297, pp. ec249
DOI: 10.1126/scisignal.2004811

In addition to controlling cell proliferation, the Hippo kinase cascade also controls postmitotic cell-fate decisions in some contexts. In mitotically active cells, activation of Hippo leads to activation of the kinase Warts (Wts), which phosphorylates the transcriptional cofactor Yorkie (Yki) to sequester Yki in the cytoplasm, thus inhibiting the expression of Yki target genes that promote proliferation and suppress apoptosis. Within the context of homeostatic growth control, Yki can also promote expression of genes that encode negative regulators of Yki activity. Jukam et al. reported that, in the fruit fly eye, Yki cooperates with its binding partner Scalloped (Sd) to promote expression of genes that specify photoreceptor fate and positively feed back on Yki activity. Postmitotic R8 photoreceptor cells irreversibly differentiate into either y-type cells, which are sensitive to green light, or p-type cells, which are sensitive to blue light. This cell-fate specification occurs stochastically, and ommatidia containing p- or y-type R8 cells are randomly distributed throughout the retina. The transcription factor Melted (Melt) specifies the pR8 fate, and the activity of Wts in some R8 cells leads to the absence of Melt and the default yR8 fate. Knocking down yki or sd in R8 photoreceptors by RNA interference (RNAi) caused nearly all R8 cells to adopt the yR8 fate, and RNAi-mediated knockdown of wts or ectopic expression of yki promoted the pR8 fate. Genetic epistasis experiments indicated that Melt promoted Yki activity and that Yki promoted expression of melt and repressed wts, thus locking some R8 cells into the p fate. This dual feedback mechanism forms a bistable switch in which the activity of Wts promotes the yR8 fate and the presence of Melt promotes the pR8 fate. This Wts-Yki-Melt circuit did not affect cell proliferation in mitotic cells of the wing or eye, and it affected R8 cell specification through a set of target genes distinct from those involved in Hippo-mediated regulation of cell proliferation. To specify R8 cells as pR8, Yki and Sd cooperated with R8-specific transcription factors, including Orthodenticle (Otd) and Traffic jam (Tj), which are orthologs of the mammalian photoreceptor determination proteins Crx and Nrl. These results illustrate how tissue-specific factors can change network topology by influencing feedback mechanisms. Yki provides negative feedback on the Hippo pathway by inhibiting its own activity in the context of cell growth control but exerts positive feedback on the Hippo pathway in the context of a terminal cell-fate specification event by promoting its own activity.

D. Jukam, B. Xie, J. Rister, D. Terrell, M. Charlton-Perkins, D. Pistillo, B. Gebelein, C. Desplan, T. Cook, Opposite feedbacks in the Hippo pathway for growth control and neural fate. Science 342, 1238016 (2013).[Abstract][Full Text]