Insulin Receptor-Mediated Signaling via Phospholipase C-γ Regulates Growth and Differentiation in Drosophila

Juan M Murillo-Maldonado,Fouad Bou Zeineddine,Rachel Stock,Juan R Riesgo-Escovar,Justin Thackeray,Efthimios M C Skoulakis

doi:10.1371/journal.pone.0028067

Juan M Murillo-Maldonado, Fouad Bou Zeineddine + Show 4 more

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https://doi.org/10.1371/journal.pone.0028067

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Abstract

Coordination between growth and patterning/differentiation is critical if appropriate final organ structure and size is to be achieved. Understanding how these two processes are regulated is therefore a fundamental and as yet incompletely answered question. Here we show through genetic analysis that the phospholipase C-γ (PLC-γ) encoded by small wing (sl) acts as such a link between growth and patterning/differentiation by modulating some MAPK outputs once activated by the insulin pathway; particularly, sl promotes growth and suppresses ectopic differentiation in the developing eye and wing, allowing cells to attain a normal size and differentiate properly. sl mutants have previously been shown to have a combination of both growth and patterning/differentiation phenotypes: small wings, ectopic wing veins, and extra R7 photoreceptor cells. We show here that PLC-γ activated by the insulin pathway participates broadly and positively during cell growth modulating EGF pathway activity, whereas in cell differentiation PLC-γ activated by the insulin receptor negatively regulates the EGF pathway. These roles require different SH2 domains of PLC-γ, and act via classic PLC-γ signaling and EGF ligand processing. By means of PLC-γ, the insulin receptor therefore modulates differentiation as well as growth. Overall, our results provide evidence that PLC-γ acts during development at a time when growth ends and differentiation begins, and is important for proper coordination of these two processes.

Highlights

During development, proper coordination of growth, proliferation, and cellular differentiation is critical for appropriate final organ structure and size
Role of SH2 domains in Sl function In order to study in more detail the relationship between Sl and receptor tyrosine kinases in the wing and eye, we examined the role of the Sl SH2 domains, which are known to be involved in the binding of phospholipase C-c (PLC-c) to RTKs in vertebrates
Sl modulates cellular growth in the wing We show, by measuring cell density, that sl mutant wings have a reduction in cell growth but not cell proliferation

Summary

Introduction

Proper coordination of growth, proliferation, and cellular differentiation is critical for appropriate final organ structure and size These processes involve signal transduction cascades that determine the spatial and temporal pattern of cellular instructions. PLC-C is an intracellular enzyme activated by a multistep process; the initial step involves membrane association via RTKs (or non-receptor tyrosine kinases) through an SH2 (Src-homology 2) domain in PLC-c with a phosphotyrosine residue in the intracellular domain of the activated receptor. Following this binding, PLC-c is phosphorylated by the RTK on one or more tyrosines and catalyzes the hydrolysis of the membrane phospholipid phosphatidylinositol (4,5) bisphosphate (PIP2), generating two intracellular messengers: inositol 1,4,5trisphosphate (IP3) and diacylglycerol (DAG). IP3 promotes the release of Ca2+ from intracellular stores, via its association with the inositol triphosphate receptor (IP3R), while DAG, together with Ca2+, activates protein kinase C (PKC) [1,2,3,4]

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