Hindsight Mediates the Role of Notch in Suppressing Hedgehog Signaling and Cell Proliferation

Abstract

Temporal and spatial regulation of proliferation and differentiation by signaling pathways is essential for animal development. Drosophila follicular epithelial cells provide an excellent model system for the study of temporal regulation of cell proliferation. In follicle cells, the Notch pathway stops proliferation and promotes a switch from the mitotic cycle to the endocycle. Here, we show that zinc-finger transcription factor Hindsight mediates the role of Notch in regulating cell differentiation and the switch of cell-cycle programs. Hindsight is required and sufficient to stop proliferation and induce the transition to the endocycle. To do so, it represses string, Cut, and Hedgehog signaling, which promote proliferation during early oogenesis. Hindsight, along with another zinc-finger protein, Tramtrack, downregulates Hedgehog signaling through transcriptional repression of cubitus interruptus. Our studies suggest that Hindsight bridges the two antagonistic pathways, Notch and Hedgehog, in the temporal regulation of follicle-cell proliferation and differentiation.

Hedgehog-stimulated stem cells depend on non-canonical activity of the Notch co-activator Mastermind

“…Interestingly, that switch is still imposed on ptc mutant follicle cells that contact the germline, and is accompanied by Notchdependent inhibition of ci expression and Hh pathway activity, which is mediated by the transcription factors Hindsight (Pebbled -FlyBase) and Tramtrack (Sun and Deng, 2007). FSC loss induced by Notch hyperactivity is also seen for ptc mutant cells and might conceivably involve an analogous mechanism, although Hindsight expression is not normally observed prior to stage 6.…”

“…The lower levels of ptc-lacZ from stage 1 onwards that are independent of smo are influenced by Ci expression (Sun and Deng, 2007) and are therefore likely to result from basal, ligandindependent pathway activity. Hence, high ptc-lacZ expression reflects selectively strong Hh signaling in the FSC but probably underestimates the gradient of Hh activity in the germarium because of β-galactosidase perdurance and a significant baseline of Hhindependent pathway activity.…”

The microRNA miR-7 regulates Tramtrack69 in a developmental switch in Drosophila follicle cells

“…To determine whether miR-7 plays a role in regulating follicle cell differentiation, we overexpressed miR-7 (Stark et al, 2003) using the flip-out-GAL4 system (Pignoni and Zipursky, 1997). The normal cell-fate changes that occur in follicle cells can be revealed by staining for two transcription factors, Cut and Hindsight (Hnt), which have complementary expression patterns in follicle cells during oogenesis (Sun and Deng, 2005;Sun and Deng, 2007). Normally, Cut is expressed in early (stages 1-6) and late oogenesis (stage 10B to later), whereas Hnt is expressed only in midoogenesis (stages 7-10A), when follicle cells are undergoing endoreplication (Fig.…”

Regulation of Pattern Formation and Gene Amplification During Drosophila Oogenesis by the miR-318 microRNA

“…Bars, 100 um. expression of another transcription factor, Hindsight (Hnt), shows the opposite pattern, being higher during the endocycles and decreasing at stage 10B (Sun and Deng 2007). Increased Cut expression and decreased Hnt expression provide markers for the transition from endocycles to gene amplification (Huang et al 2013).…”