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, 247 (2), 315-322

Adult Functions for the Drosophila DHR78 Nuclear Receptor

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Adult Functions for the Drosophila DHR78 Nuclear Receptor

Stefanie Marxreiter et al. Dev Dyn.

Abstract

Background: The Testicular Receptors 2 and 4 (TR2, TR4) comprise a small subfamily of orphan nuclear receptors. Genetic studies in mouse models have identified roles for TR4 in developmental progression, fertility, brain development, and metabolism, as well as genetic redundancy with TR2. Here we study the adult functions of the single Drosophila member of this subfamily, DHR78, with the goal of defining its ancestral functions in the absence of genetic redundancy.

Results: We show that DHR78 mutants have a shortened lifespan, reduced motility, and mated DHR78 mutant females display a reduced feeding rate. Transcriptional profiling reveals a major role for DHR78 in promoting the expression of genes that are expressed in the midgut, suggesting that it contributes to nutrient uptake. We also identify roles for DHR78 in maintaining the expression of genes in the ecdysone and Notch signaling pathways.

Conclusions: This study provides a new context for linking the molecular activity of the TR orphan nuclear receptors with their complex roles in adult physiology and lifespan. Developmental Dynamics 247:315-322, 2018. © 2017 Wiley Periodicals, Inc.

Keywords: gene expression; metabolism; nuclear receptor; transcription.

Figures

Fig. 1
Fig. 1. DHR78 mutants display larval lethality and tracheal defects
(A) The percent of surviving w1118 controls and DHR781/3 mutants are shown at different time points representing the stage of control animals as either first instar larvae (L1), second instars (L2), early or late third instars (L3), prepupae (PP), or pupae. Most DHR78 mutant larvae are dead when controls pupariate. DHR78 mutants progress normally into the second instar, when they begin to display roving behavior, developmental asynchrony, and lethality as second or early third instar larvae (Fisk and Thummel, 1998). (B) DHR78 mutants that reach the third instar are significantly smaller than w1118 controls and (C) display tracheal molting defects. (D) Late second instar w1118 controls (blue) and DHR781/3 mutants (red) display reduced glycogen and triglyceride stores, likely due to a starvation response from their roving behavior. Data was normalized to protein levels to account for size differences between controls and mutants, then graphed relative to control levels. Data are graphically represented as box plots. * p<0.05, ** p<0.005
Fig. 2
Fig. 2. Rescued DHR78 mutants display shortened lifespans and motility defects
Lifespan was measured in four control genotypes (black, grey, grey dotted line, and blue) and rescued DHR78 mutant (red) males (A) and females (B). n > 55 flies per genotype. p<0.001 for both lifespan experiments, comparing btl>DHR78 controls (blue) to rescued DHR78 mutants (red). (C,D) btl>DHR78 controls (blue) and rescued DHR78 mutants (btl>DHR78; DHR781/3, red) as either males (C) or females (D) display reduced motility when tested with a negative geotaxis assay. Data are graphically represented as box plots. n = 15–35 flies per genotype. ***p<0.0005
Fig. 3
Fig. 3. DHR78 mutant mated females display a reduced feeding rate
Samples were collected from four control genotypes (black, dark grey, light grey, and blue) and rescued DHR78 mutants (btl>DHR78; DHR781/3; red) as either males (A–C) or mated females (D–F), and assayed for glucose (A,D), glycogen (B,E), or triglycerides (C,F; TAG). n = 11–24 samples for each group. Data are graphically represented as box plots, relative to the metabolite level in btl>DHR78 controls (blue). (G) btl>DHR78 controls (blue) and rescued DHR78 mutants (btl>DHR78; DHR781/3, red) were assayed for feeding rate by measuring the amount of radioactive food ingested after an overnight fast. Data is combined from two separate experiments for each condition. *** p<0.0005
Fig. 4
Fig. 4. Many intestinal genes are expressed at reduced levels in DHR78 mutants
Heat maps are depicted for genes that change their expression level in DHR78 mutant females. Each row of the heat map represents a specific tissue, and each column represents an individual gene either (A) up-regulated or (B) down-regulated in mutants. The color corresponds to the expression level for that gene in wild-type tissues as reported by FlyAtlas (Robinson et al., 2013), with black representing little or no expression and green representing higher expression. More broadly expressed genes are shown on the right side of the heat map. Many genes that are abundantly expressed in the midgut of wild-type flies are down-regulated in DHR78 mutants.

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