Topology-driven protein-protein interaction network analysis detects genetic sub-networks regulating reproductive capacity.

Tarun Kumar,Leo Blondel,Cassandra G Extavour

doi:10.7554/elife.54082

Abstract

Understanding the genetic regulation of organ structure is a fundamental problem in developmental biology. Here, we use egg-producing structures of insect ovaries, called ovarioles, to deduce systems-level gene regulatory relationships from quantitative functional genetic analysis. We previously showed that Hippo signalling, a conserved regulator of animal organ size, regulates ovariole number in Drosophila melanogaster. To comprehensively determine how Hippo signalling interacts with other pathways in this regulation, we screened all known signalling pathway genes, and identified Hpo-dependent and Hpo-independent signalling requirements. Network analysis of known protein-protein interactions among screen results identified independent gene regulatory sub-networks regulating one or both of ovariole number and egg laying. These sub-networks predict involvement of previously uncharacterised genes with higher accuracy than the original candidate screen. This shows that network analysis combining functional genetic and large-scale interaction data can predict function of novel genes regulating development.

Highlights

30 The final shape and size of an organ is critical to organismal function and viability
Regulation of ovariole number is largely dependent on the specification of the terminal filament cells (TFCs) and their rearrangement into terminal filament (TF) (Sarikaya and Extavour, 2015). 72 We previously showed that the regulation of both TFC and TF number is dependent on the Hippo signalling pathway (Sarikaya and Extavour, 2015), a pan-metazoan regulator of organ and tissue size (Hilman and Gat, 2011; Sebe-Pedros et al, 2012)
In the D. melanogaster larval ovary, loss of Hpo in the somatic cells causes an increase in nuclear Yki, leading to an increase in TFCs, TFs, ovariole number and egg laying in adults (Sarikaya and Extavour, 2015). 82 Production of fertile eggs from a stereotypic number of ovarioles requires a spatially and temporally coordinated interplay of signalling between the somatic and germ line cells of the ovary

Summary

Introduction

30 The final shape and size of an organ is critical to organismal function and viability. 37 The Drosophila melanogaster female reproductive system is a useful paradigm to study quantitative anatomical traits In these organs, the effects of multiple genes and the environment combine to produce a quantitative phenotype: a species-specific average number of egg[40] producing ovarian tubes called ovarioles. In the D. melanogaster larval ovary, loss of Hpo in the somatic cells causes an increase in nuclear Yki, leading to an increase in TFCs, TFs, ovariole number and egg laying in adults (Sarikaya and Extavour, 2015). Functional testing showed that these novel genes affect ovariole number and/or egg laying, providing us with a novel in silico method to identify target genes that affect ovarian development and function We use these findings to propose putative developmental regulatory networks underlying one or both of ovariole formation and egg laying

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Conclusion