Regulation of Yorkie activity in Drosophila imaginal discs by the Hedgehog receptor gene patched

Abstract

The Hedgehog (Hh) pathway was first defined by its role in segment polarity in the Drosophila melanogaster embryonic epidermis and has since been linked to many aspects of vertebrate development and disease. In humans, mutation of the Patched1 (PTCH1) gene, which encodes an inhibitor of Hh signaling, lead to tumors of the skin and pediatric brain. Despite the high level of conservation between the vertebrate and invertebrate Hh pathways, studies in Drosophila have yet to find direct evidence that ptc limits organ size. Here we report identification of Drosophila ptc in a screen for mutations that require a synergistic apoptotic block in order to drive overgrowth. Developing imaginal discs containing clones of ptc mutant cells immortalized by the concurrent loss of the Apaf-1-related killer (Ark) gene are overgrown due, in large part, to the overgrowth of wild type portions of these discs. This phenotype correlates with overexpression of the morphogen Dpp in ptc,Ark double-mutant cells, leading to elevated phosphorylation of the Dpp pathway effector Mad (p-Mad) in cells surrounding ptc,Ark mutant clones. p-Mad functions with the Hippo pathway oncoprotein Yorkie (Yki) to induce expression of the pro-growth/anti-apoptotic microRNA bantam. Accordingly, Yki activity is elevated among wild type cells surrounding ptc,Ark clones and alleles of bantam and yki dominantly suppress the enlarged-disc phenotype produced by loss of ptc. These data suggest that ptc can regulate Yki in a non-cell autonomous manner and reveal an intercellular link between the Hh and Hippo pathways that may contribute to growth-regulatory properties of the Hh pathway in development and disease.

Non-cell autonomous control of apoptosis by ligand-independent Hedgehog signaling in Drosophila

“…For example, mosaic wing discs, which contain clones of activated N or are doubly mutant for ptc and ark (Apaf-1-related killer), stimulate Hippo/ Warts/Yorkie signaling. 35,56 These responses appear to be a The mutant cell accumulates CiA, which promotes autonomous N activity (purple arrow) and stimulates Dl expression (green arrow). Autonomous N signaling releases an unknown extracellular factor that promotes transcription of diap1 in the first signal-receiving non-mutant cell, cell B.…”

Hippo vs. Crab: tissue‐specific functions of the mammalian Hippo pathway

“…; Kagey et al . ). In addition, GLI family zinc finger 2 (GLI2), an SHH signaling mediator, functions downstream of YAP1 to regulate neuronal differentiation (Lin et al .…”

“…; Kagey et al . ). Overexpression of YAP1 or TEAD promotes cell cycle progression and migration, blocks neuronal differentiation by triggering cyclin D1 and PAX3 expression and mediates resistance to cisplatin‐induced apoptosis in vitro (Milewski et al .…”

The Mapping and Characterization of <i>Cruella (Cru)</i>, a Novel Allele of <i>Capping Protein α (Cpa)</i>, Identified from a Conditional Screen for Negative Regulators of Cell Growth and Cell Division

“…The experiments performed stem from a conditional EMS mutagenesis screen of chromosome 2R for abnormalities in growth and development [11]. To study these muta- …”

“…In the present study, we utilized a "two-hit" Flp/FRT screen on chromosome 2R. We began the screen with the ;FRT42D, ark 82 chromosome, which would block the canonical apoptotic pathway in homozygous mutant tissue, and then induced the mutations with EMS [11]. This screen, along with several others, has identified a conditional class of regulators of cell growth and cell division that are dependent on a block in apoptosis for phenotypic changes [11]- [13] …”