The Hippo Effector Yorkie Controls Normal Tissue Growth by Antagonizing Scalloped-Mediated Default Repression

Abstract

The Hippo tumor suppressor pathway restricts tissue growth by inactivating the transcriptional coactivator Yki. Although Sd has been implicated as a DNA-binding transcription factor partner for Yki and can genetically account for gain-of-function Yki phenotypes, how Yki regulates normal tissue growth remains a long-standing puzzle since Sd, unlike Yki, is dispensable for normal growth in most Drosophila tissues. Here we show that the yki mutant phenotypes in multiple developmental contexts are rescued by inactivation of Sd, suggesting that Sd functions as a default repressor and that Yki promotes normal tissue growth by relieving Sd-mediated default repression. We further identify Tgi as a cofactor involved in Sd's default repressor function and demonstrate that the mammalian orthologue of Tgi potently suppresses the YAP oncoprotein in transgenic mice. These findings fill a major gap in Hippo-mediated transcriptional regulation and open up new possibilities for modulating the YAP oncoprotein in cancer and regenerative medicine.

Ci antagonizes Hippo signaling in the somatic cells of the ovary to drive germline stem cell differentiation

“…As shown in Figure 3G-3H, like Tgi, overxpression of Vg disrupted the interaction of Yki with Sd in a dose-dependent manner. We noted that, while it indeed impaired the interaction of Tgi with Sd ( Figure 3I) [24], overexpression of Yki failed to disrupt the Vg-Sd interaction under our experimental conditions (Supplementary information, Figure S3D), suggesting that Yki primarily competes with Tgi to bind Sd. We next performed further genetic tests, and found that EC-specific tgi knockdown suppressed the tumorous germarium phenotype induced by overexpression of Vg in ECs ( Figure 3J-3K).…”

“…Given the recently proposed default repression model [24], we tested whether depletion of sd could reverse yki knockdown-induced tumorous germarium phenotype, and found that it indeed did ( Figure 2D-2E). Notably, we found that while yki knockdown in ECs caused female sterility, yki and sd double-knockdown females were fertile and exhibited normal germline development (Supplementary information, Figure S2B-S2C).…”

“…Recent studies have identified Tgi, a Tondu-domain-containing protein, as an Sd cofactor in the default repressing complex to regulate tissue growth in Drosophila imaginal discs [24,25]. We followed the above protocol to test whether Tgi contributes to the Sd-mediated default repression in ECs.…”

“…In the absence of the upstream kinase cascade signaling, Yki is therefore released from the control of Hippo signaling and translocates into the nucleus, where it binds to the transcription factor, Scalloped (Sd), to activate downstream target genes including diap1, cyclin E and bantam, thereby promoting cell proliferation and inhibiting cell apoptosis [21][22][23]. Recently, an elegant study demonstrated that the primary role of Yki in normal tissue growth is to antagonize Sd-mediated transcriptional repression, where Tgi, a Tondu-domain-containing protein, functions as an Sd-associating factor to suppress the expression of Yki target genes [24]. In this default repression model, low-level Yki activation in the nucleus reverses Sd-mediated default repression, thus enabling normal tissue growth.…”

“…In this default repression model, low-level Yki activation in the nucleus reverses Sd-mediated default repression, thus enabling normal tissue growth. In contrast, activation of the Hippo pathway turns off the nuclear functions of Yki and thus maintains Sd-mediated default transcriptional repression, which precludes cell growth [24,25]. Thus, balanced regulation of Yki activation and Sd-mediated default repression is critical for organ size control during development, and is possibly important in other biological processes such as stem cell regulation and tumorigenesis [13,20].…”