Inhibition of Notch signaling by the p105 and p180 subunits of Drosophila chromatin assembly factor 1 is required for follicle cell proliferation

Abstract

Chromatin assembly factor 1 (CAF1), a histone chaperone that mediates the deposition of histone H3/H4 onto newly synthesized DNA, is involved in Notch signaling activation during Drosophila wing imaginal disc development. Here, we report another side of CAF1, wherein the subunits CAF1-p105 and CAF1-p180 (also known as CAF1-105 and CAF1-180, respectively) inhibit expression of Notch target genes and show this is required for proliferation of Drosophila ovarian follicle cells. Loss-of-function of either CAF1-p105 or CAF1-p180 caused premature activation of Notch signaling reporters and early expression of the Notch target Hindsight (Hnt, also known as Pebbled), leading to Cut downregulation and inhibition of follicle cell mitosis. Our studies further show Notch is functionally responsible for these phenotypes observed in both the CAF1-p105-and CAF1-p180-deficient follicle cells. Moreover, we reveal that CAF1-p105-and CAF1-p180-dependent Cut expression is essential for inhibiting Hnt expression in follicle cells during their mitotic stage. These findings together indicate a novel negative-feedback regulatory loop between Cut and Hnt underlying CAF1-p105 and CAF-p180 regulation, which is crucial for follicle cell differentiation. In conclusion, our studies suggest CAF1 plays a dual role to sustain cell proliferation by positively or negatively regulating Drosophila Notch signaling in a tissue-context-dependent manner.

Downregulation of homeodomain protein Cut is essential for follicle maturation and ovulation

“…Loss of Hnt leads to extended Cut expression in stage-7 follicle cells, whereas misexpression of Hnt in earlier follicle cells can drive premature downregulation of Cut. It is interesting that Cut knockdown in mitotic follicle cells also leads to premature upregulation of Hnt (Lo et al, 2019), indicating that Hnt and Cut antagonize each other to regulate the M/E switch. Hnt/Cut and Ttk69 do not regulate each other at the M/E transition (Sun and Deng, 2007); however, Ttk69 acts upstream of Hnt and Cut in the E/A switch during mid-oogenesis.…”

“…The transition from mitotic cycle to endocycle (M/E transition) is induced by Notch signaling, which activates the zincfinger transcription factor Hindsight (Hnt) to downregulate Cut and inhibit Hedgehog signaling (Deng et al, 2001;Lopez-Schier and St. Johnston, 2001;Sun and Deng, 2007). In the last decade, multiple factors have been found to regulate Notch signaling and the M/E transition (Domanitskaya and Schüpbach, 2012;Fic et al, 2019;Jia et al, 2015;Jouandin et al, 2014;Lee and Spradling, 2014;Lo et al, 2019;Poulton et al, 2011;Starble and Pokrywka, 2018;Vaccari et al, 2010). At the endocycle/gene amplification (E/A) transition, downregulation of Notch signaling permits the activation of ecdysteroid signaling, which upregulates another zincfinger transcription factor Tramtrack-69 (Ttk69) at stage 10B (Sun et al, 2008).…”