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

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.

Distinct gene expression dynamics in germ line and somatic tissue during ovariole morphogenesis in Drosophila melanogaster

“…Our results show that in the late stage of somatic cells there is an increase in expression of genes involved in multiple signaling pathways, including the Wnt, MAPK, Hippo, Hedgehog, FoxO, TGF, and Notch pathways ( Figure 5E ). The molecular mechanisms of all these signaling pathways during larval ovary development have not yet been extensively studied, but all of them have been functionally implicated in ovariole number determination by a large-scale genetic screen ( Kumar et al 2020 ).…”

“…Although all major conserved animal signaling pathways are known to be involved in ovarian morphogenesis ( Twombly et al 1996 ; Cohen et al 2002 ; Huang et al 2005 ; Song et al 2007 ; Gancz and Gilboa 2013 ; Green and Extavour 2014 ; Sarikaya and Extavour 2015 ; Kumar et al 2020 ), a systematic gene expression profile of a developing ovary is lacking. Such system-wide gene expression data for the ovary throughout terminal filament morphogenesis, including the potentially distinct transcriptional profiles of germ cells and somatic cells, could shed light on the processes involved in the maintenance of cell types necessary to shape the ovary and control the number of ovarioles.…”

Properties, Structures, and Physiological Roles of Three Types of Anion Channels Molecularly Identified in the 2010’s

“…Also, a number of disorders are found in recent studies using specific cell- or tissue-targeted Lrrc8a knockout mice. For example, impaired glucose tolerance and insulin resistance are caused by conditional knockout of Lrrc8a expressing in adipocytes ( Zhang et al, 2017 ), pancreatic β cells ( Kang et al, 2018 ), and skeletal muscle cells ( Kumar et al, 2020 ); male infertility by germ cell-specific Lrrc8a disruption ( Lück et al, 2018 ); angiotensin-II-stimulated hypertension by endothelial-targeted Lrrc8a knockout ( Alghanem et al, 2021 ); and brain hyperexcitability coupled to astrogliosis by brain-specific Lrrc8a disruption ( Wilson et al, 2021 ). However, it is not known whether these dysfunctions are caused by disordered anion-conductive activities of LRRC8A or non-conductive protein-protein interactions.…”

Network organization of the plant immune system: from pathogen perception to robust defense induction

“…One of the main outputs of systems biology of plantpathogen interactions may be the breakthrough identification of major regulators of the immune system, at the scale of genes, proteins, or metabolites, whose function can be experimentally tested. This approach has proven to be fruitful for providing new insights into the mammalian immune system and developmental processes by identifying new genes through topology-driven network analysis (Kumar et al, 2020) combined with RNA interference or CRISPR perturbation screening (Shi et al, 2020). In plants, such approaches remain scarce.…”