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Nuclear receptors — a perspective from Drosophila

Key Points

  • The fruitfly Drosophila melanogaster has only 18 nuclear-receptor genes — far fewer than any other genetic model organism and representing all the main subfamilies of vertebrate receptors.

  • Many aspects of nuclear-receptor regulation and function have been conserved through evolution from insects to humans.

  • Hormones and nuclear receptors control maturation in both insects and humans, and studies in D. melanogaster provide a molecular basis for understanding how maturation is regulated.

  • Many direct targets of the ecdysone receptor are themselves members of the nuclear-receptor superfamily.

  • Like their mammalian orthologues ROR (RAR-related orphan receptor) and REV–ERBA, D. melanogaster DHR3 (Drosophila hormone receptor 3) and E75 can exert antagonistic functions.

  • The D. melanogaster orthologues of mammalian PNR (photoreceptor-specific nuclear receptor) and TLX (mammalian orthologue of tailless) control neuronal development, paralleling the functions of their vertebrate counterparts.

  • DHR38, DHR78, DHR96, HNF4 (Drosophila hepatic nuclear factor 4), and fly ERR (Drosophila oestrogen-related receptor) might have ligand-regulated activities.

  • Like its human orthologue NR4A2 (also known as NURR1), DHR38 lacks a conventional co-activator binding site and a ligand-binding pocket. Its activation by ecdysteroids, however, suggests that this class of receptors can be ligand-regulated through a novel mechanism.

  • Future studies of D. melanogaster nuclear receptors will exploit new technologies such as the GAL4–LBD 'ligand-trap' system and mass spectrometry to identify new ligands.

  • Future genetic analysis of fly nuclear receptors is likely to provide new insights into insect physiology and endocrinology, as well as new directions for insect pest control.

Abstract

Nuclear receptors are ancient ligand-regulated transcription factors that control key metabolic and developmental pathways. The fruitfly Drosophila melanogaster has only 18 nuclear-receptor genes — far fewer than any other genetic model organism and representing all 6 subfamilies of vertebrate receptors. These unique attributes establish the fly as an ideal system for studying the regulation and function of nuclear receptors during development. Here, we review recent breakthroughs in our understanding of D. melanogaster nuclear receptors, and interpret these results in light of findings from their evolutionarily conserved vertebrate homologues.

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Figure 1: Molecular mechanisms of nuclear-receptor regulation.
Figure 2: Temporal profiles of 20E-regulated nuclear-receptor gene expression.
Figure 3: The GAL4–LBD ligand-trap system for in vivo detection of nuclear receptor ligands.

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Acknowledgements

We thank K. Baker for critical comments on the manuscript and we apologize to authors whose work could not be cited owing to length restrictions. Research in our laboratory is supported by the US National Institutes of Health and the Howard Hughes Medical Institute.

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DATABASES

Entrez

COUP-TF1

DHR3

DHR4

DHR38

DHR39

DHR78

DHR96

dsf

EcR

ERR

E75

E78

ftz-f1

Hnf4

NR4A2

svp

tll

Tlx

USP

OMIM

MODY

FURTHER INFORMATION

Carl Thummel's laboratory

Glossary

CLADE

A group of organisms that includes common ancestor and all of its descendants, representing a distinct branch on a phylogenetic tree.

MONOPHYLETIC

A natural clade that includes an ancestral species or gene and all of its descendants.

HOLOMETABOLOUS

Refers to insects that interpose a pupal stage between the final larval stage and the adult.

ECDYSTEROIDS

Insect steroids that are similar in structure to the moulting hormone ecdysone.

PROTHORACIC GLAND

An insect endocrine gland that produces ecdysteroids.

HAEMOLYMPH

Insect blood.

DOMINANT-NEGATIVE

A mutation in a gene that interferes with the function of its wild-type counterpart.

GERMBAND RETRACTION

A large-scale morphogenetic movement during Drosophila gastrulation that results in the repositioning of the future posterior segments at the posterior end of the embryo.

HEAD INVOLUTION

Morphogenetic reorganization of the embryonic head region in D. melanogaster.

CUTICLE

A chitinous secretion of epidermal cells that covers the outside of the insect body, providing protection and support.

IMAGINAL DISC

An epithelial sheet that gives rise to external adult structures during insect metamorphosis, including the wings, eyes and antennae.

PRIMARY-RESPONSE GENE

A gene that is regulated directly by a transcription factor in response to a signal.

POLYTENE CHROMOSOME

A giant chromosome that is formed by many rounds of DNA replication in the absence of cytokinesis. The replicated DNA molecules are tightly aligned along their length in precise register, creating a transcriptionally active chromosome with a diagnostic banding pattern that is easily visualized through light microscopy.

GERMLINE CLONE

The germline lineage, or the offspring of this lineage, that carries a homozygous mutant allele that was generated by mitotic recombination in a heterozygous female. This use of these clones enables the production of progeny that lack a maternal contribution of the gene in question.

PREPUPA

The developmental stage in Drosophila melanogaster that follows pupariation and precedes adult head eversion.

PUPARIATION

Puparium formation. The larval–prepupal transition.

GAP GENE

Genes that direct the development of several contiguous segments in the early fly embryo.

OPTIC CUP

A cup-like depression in the optic vesicle that develops into the sensory (neural) and pigmented layers of the retina.

OMMATIDIUM

The light-gathering and sensory unit of the insect compound eye.

FAT BODY

The principal organ of intermediary metabolism in insects. Similar in function to the vertebrate liver.

MALPIGHIAN TUBULES

The excretory and osmoregulatory organ of insects that opens near the junction of the midgut and hindgut.

VITELLOGENIN

A protein produced in the fat body of the female insect that is stored in the yolk of oocytes.

DIAPAUSE

A period of inactivity and cessation of growth or development, accompanied by greatly reduced metabolic activity.

MASS SPECTROMETRY

A method that provides accurate information about the molecular mass and structure of molecules. It can identify and quantify extremely small amounts of drugs, hormones or metabolites.

MICRORNA

Small non-coding RNAs that can control the expression of target mRNAs.

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King-Jones, K., Thummel, C. Nuclear receptors — a perspective from Drosophila. Nat Rev Genet 6, 311–323 (2005). https://doi.org/10.1038/nrg1581

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