Drosophila Ribosomal Protein Mutants Control Tissue Growth Non-Autonomously via Effects on the Prothoracic Gland and Ecdysone

Jane I Lin,Steven J Marygold,Richard B Pearson,Naomi C Mitchell,Cherryl D Walker,Leonie M Quinn,Ross D Hannan,Elly Tchoubrieva,Mary J Stewart,George Thomas,Marina Kalcina,Sally J Leevers,Norbert Perrimon

doi:10.1371/journal.pgen.1002408

Abstract

The ribosome is critical for all aspects of cell growth due to its essential role in protein synthesis. Paradoxically, many Ribosomal proteins (Rps) act as tumour suppressors in Drosophila and vertebrates. To examine how reductions in Rps could lead to tissue overgrowth, we took advantage of the observation that an RpS6 mutant dominantly suppresses the small rough eye phenotype in a cyclin E hypomorphic mutant (cycEJP). We demonstrated that the suppression of cycEJP by the RpS6 mutant is not a consequence of restoring CycE protein levels or activity in the eye imaginal tissue. Rather, the use of UAS-RpS6 RNAi transgenics revealed that the suppression of cycEJP is exerted via a mechanism extrinsic to the eye, whereby reduced Rp levels in the prothoracic gland decreases the activity of ecdysone, the steroid hormone, delaying developmental timing and hence allowing time for tissue and organ overgrowth. These data provide for the first time a rationale to explain the counter-intuitive organ overgrowth phenotypes observed for certain members of the Minute class of Drosophila Rp mutants. They also demonstrate how Rp mutants can affect growth and development cell non-autonomously.

Highlights

One of the early phenotypic classes identified in Drosophila was the Minutes, which were classified based on the heterozygous adults having short slender bristles on the body, a generally smaller body size and a delay in the onset of metamorphosis [1]
Ribosomes are required for protein synthesis, which is essential for cell growth and division, mutations that reduce Ribosomal proteins (Rps) expression would be expected to limit cell growth
The underlying mechanism(s) behind these unexpected overgrowth phenotypes despite impairment of ribosome biogenesis has remained obscure. We have addressed this question using the power of Drosophila genetics, taking advantage of our observation that four different Rp mutants, or Minutes, are able to suppress a small rough eye phenotype associated with a mutation of the essential controller of cell proliferation cyclin E

Summary

Introduction

One of the early phenotypic classes identified in Drosophila was the Minutes, which were classified based on the heterozygous adults having short slender bristles on the body, a generally smaller body size and a delay in the onset of metamorphosis [1]. Rps are essential for the assembly and optimal functioning of the ribosome and are, obligate for protein synthesis and cell growth (reviewed in [5,6]). Due to their essential role in ribosome biogenesis, mutations that reduce Rp expression would be expected to limit cell growth. This cell intrinsic requirement for Rps explains many aspects of the Minute phenotype, such as the thin bristles and reduced body size in some Minutes. Other aspects of the Minute phenotype have remained enigmatic

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Conclusion