Nuclear Receptor DHR4 Controls the Timing of Steroid Hormone Pulses During Drosophila Development

Qiuxiang Ou,Adam Magico,Kirst King-Jones,David S Schneider

doi:10.1371/journal.pbio.1001160

Abstract

Author SummarySteroid hormones play fundamental roles in development and disease. They are often released as pulses, thereby orchestrating multiple physiological and developmental changes throughout the body. Hormone pulses must be regulated in a way so that they have a defined beginning, peak, and end. In Drosophila, pulses of the steroid hormone ecdysone govern all major developmental transitions, such as the molts or the transformation of a larva to a pupa. While we have a relatively good understanding of how an ecdysone pulse is initiated, little is known about how hormone production is turned off. In this study, we identify a critical regulator of this process, the nuclear receptor DHR4. When we interfere with the function of DHR4 specifically in the ecdysone-producing gland, we find that larvae develop much faster than normal, and that this is caused by the inability to turn off ecdysone production. We show that DHR4 oscillates between cytoplasm and nucleus of ecdysone-producing cells under the control of a neuropeptide that regulates ecdysone production. When the neuropeptide pathway is inactive, DHR4 enters the nucleus and represses another gene, Cyp6t3, for which we show a novel role in the production of ecdysone.

Highlights

The development of higher organisms is fundamentally dependent on the precise progression of specific gene programs, and even minor differences in the timing of these events can be fatal [1,2]
Based on ring gland (RG)-specific microarrays, we show that Cyp6t3 is a cytochrome P450 gene expressed in the RG, and that the gene is normally repressed by Drosophila Hormone Receptor 4 (DHR4)
We propose a model by which DHR4 inhibits ecdysone synthesis through the regulation of cytochrome P450 genes, and whereby prothoracicotopic hormone (PTTH) activity triggers the translocation of DHR4 from the nucleus to the cytoplasm to temporarily relieve this inhibition, allowing for ecdysone pulses to occur

Summary

Introduction

The development of higher organisms is fundamentally dependent on the precise progression of specific gene programs, and even minor differences in the timing of these events can be fatal [1,2]. The release of steroid hormones from their respective glands is temporally controlled, resulting in systemic pulses of defined duration [4] This raises the interesting question as to how onset, size, and duration of hormone pulses are regulated, since all these variables will affect target tissue responses. In Drosophila melanogaster, at least three minor ecdysone pulses occur in third instar (L3) larvae These pulses are required for important changes in physiology and behavior, including the commitment of a larva to a pupal fate (critical weight checkpoint), the induction of the Sgs (‘‘glue’’) genes that serve to attach the pupa to a solid substrate, and the switch from feeding to wandering behavior [7,8,9,10,11]. Critical weight is a physiological checkpoint that determines whether the larva has acquired sufficient resources to

Author Summary

Results

Discussion

Materials and Methods

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