Coordinated growth of linked epithelia is mediated by the Hippo pathway

Abstract

An epithelium in a living organism seldom develops in isolation. Rather, most epithelia are tethered to other epithelial or non-epithelial tissues, necessitating growth coordination between layers. We investigated how two tethered epithelial layers of theDrosophilalarval wing imaginal disc, the disc proper (DP) and the peripodial epithelium (PE), coordinate their growth. DP growth is driven by the morphogens Hedgehog (Hh) and Dpp, but regulation of PE growth is poorly understood. We find that the PE adapts to changes in growth rates of the DP, but not vice versa, thus favoring a leader and follower mechanism. Moreover, PE growth can occur by cell shape changes, even when proliferation is inhibited. While Hh and Dpp pattern gene expression in both layers, growth of the DP is exquisitely sensitive to Dpp levels, while growth of the PE is not; the PE can achieve an appropriate size even when Dpp signaling is inhibited. Instead, both the growth of the PE and its accompanying cell shape changes require the activity of two components of the mechanosensitive Hippo pathway, the DNA-binding protein Scalloped (Sd) and its co-activator (Yki), which could allow the PE to sense and respond to forces generated by DP growth. Thus, an increased reliance on mechanically-dependent growth mediated by the Hippo pathway, at the expense of morphogen-dependent growth, enables the PE to evade layer-intrinsic growth control mechanisms and coordinate its growth with the DP. This provides a potential paradigm for growth coordination between different components of a developing organ.

Hippo effector, Yorkie, is a Tumor Suppressor in SelectDrosophilaSquamous Epithelia

“…Therefore, in the subsequent part of this study, we have used nuclear translocation of Yki::GFP or Diap1-lacZ as a readout for Yki signaling. These cell flattening-linked hallmarks of MAG are reminiscent of those seen in the adult ovarian follicular and peripodial epithelia (Fletcher et al, 2018; Friesen and Hariharan, 2023; Kowalczyk et al, 2022).…”

“…In this regard, it is well-recognized that the nature of extracellular signals may trigger specific responses within cells (López-Maury et al, 2008): for instance, diverse gene expression programs based on disparate mechanosensory cues arising from substrate. The contrasting outcomes of yki knockdown in the SEs from non-tubular (Fletcher et al, 2018;Friesen and Hariharan, 2023) and tubular organs (this report) likely exemplify this scenario.…”

“…Previously, in Drosophila, chronic nuclear Yki signaling was shown in the squamous epithelia (SE) of the peripodial membrane of imaginal discs (Fletcher et al, 2018; Friesen and Hariharan, 2023) and ovarian follicles (Borreguero-Muñoz et al, 2019; Fletcher et al, 2018), as a fallout of their mechanical strain. Here, we have further asked if SE of the adult male accessory gland, MAG (Heifetz et al, 2000), too, displays nuclear Yki signaling.…”

“…Previously, it was shown that the knockdown of nuclear Yki signaling in mechanically strained epithelia—like the peripodial layer of imaginal discs or follicular epithelium enveloping the growing oocytes—reduces cell size (Fletcher et al, 2018; Friesen and Hariharan, 2023). By contrast, in MAG SE, loss of Yki signaling induced hypertrophy within two days of Yki signaling knockdown: that is, in a 5-day-old adult ( ov>yki-IR, Fig.…”

“…These include mammalian cholangiocytes (Kowalczyk et al, 2022), endothelial cells (Dupont et al, 2011; Hooglugt et al, 2021), stretched fibroblasts (Calvo et al, 2013; Liu et al, 2015), lung alveolar AT1 cells (Li et al, 2018; Mahoney et al, 2014), and stretched retinal pigment epithelial cells of zebrafish (Moreno-Marmol et al, 2018). In Drosophila, Yki shows perpetual nuclear signaling in the SE of peripodium of imaginal discs or follicles egg chambers (Borreguero-Muñoz et al, 2019; Fletcher et al, 2018; Friesen and Hariharan, 2023), wherein its loss compromises cell shape and size.…”