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Cells,
2020]
Nuclear hormone receptors are a family of transcription factors regulated by small molecules derived from the endogenous metabolism or diet. There are forty-eight nuclear hormone receptors in the human genome, twenty of which are still orphans. In this review, we make a brief historical journey from the first observations by Berthold in 1849 to the era of orphan receptors that began with the sequencing of the <i>Caenorhabditis elegans</i> genome in 1998. We discuss the evolution of nuclear hormone receptors and the putative ancestral ligands as well as how the ligand universe has expanded over time. This leads us to define four classes of metabolites-fatty acids, terpenoids, porphyrins and amino acid derivatives-that generate all known ligands for nuclear hormone receptors. We conclude by discussing the ongoing efforts to identify new classes of ligands for orphan receptors.
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[
Science,
1998]
Neurotransmitter receptors, neurotransmitter synthesis and release pathways, and heterotrimeric GTP-binding protein (G protein)-coupled second messenger pathways are highly conserved between Caenorhabditis elegans and mammals, but gap junctions and chemosensory receptors have independent origins in vertebrates and nematodes. Most ion channels are similar to vertebrate channels but there are no predicted voltage-activated sodium channels. The C. elegans genome encodes at least 80 potassium channels, 90 neurotransmitter-gated ion channels, 50 peptide receptors, and up to 1000 orphan receptors that may be chemoreceptors. For many gene families, C. elegans has both conventional members and divergent outliers with weak homology to known genes; these outliers may provide insights into previously unknown functions of conserved protein families.
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Gen Comp Endocrinol,
2008]
In the recent decade, tremendous progress has been realized in insect endocrinology as the result of the application of a variety of advanced methods in neuropeptidome- and receptor research. Hormones of which the existence had been shown by bioassays four decades ago, e.g. bursicon (a member of the glycoprotein hormone family) and pupariation factor (Neb-pyrokinin 2, a myotropin), could be identified, along with their respective receptors. In control of diurnal rhythms, clock genes got company from the neuropeptide Pigment Dispersing Factor (PDF), of which the receptor could also be identified. The discovery of Inka cells and their function in metamorphosis was a true hallmark. Analysis of the genomes of Caenorhabditis elegans, Drosophila melanogaster and Apis mellifera yielded about 75, 100 and 200 genes coding for putative signaling peptides, respectively, corresponding to approximately 57, 100 and 100 peptides of which the expression could already be proven by means of mass spectrometry. The comparative approach invertebrates-vertebrates recently yielded indications for the existence of counterparts in insects for prolactin, atrial natriuretic hormone and Growth Hormone Releasing Hormone (GRH). Substantial progress has been realized in identifying the Halloween genes, a membrane receptor(s) for ecdysteroids, a nuclear receptor for methylfarnesoate, and dozens of GPCRs for insect neuropeptides. The major remaining challenges concern the making match numerous orphan GPCRs with orphan peptidic ligands, and elucidating their functions. Furthermore, the endocrine control of growth, feeding-digestion, and of sexual differentiation, in particular of males, is still poorly understood. The finding that the prothoracic glands produce an autocrine factor with growth factor-like properties and secrete proteins necessitates a reevaluation of their role in development.
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Medicina (B Aires),
2009]
Green fluorescent protein (GFP) is a protein produced by the jellyfish Aequorea victoria, that emits bioluminescence in the green zone of the visible spectrum. The GFP gene has been cloned and is used in molecular biology as a marker. The three researchers that participated independently in elucidating the structure and function of this and its related proteins, Drs. Shimomura, Chalfie and Tsien were awarded the Nobel Prize in Chemistry 2008. Dr. Shimomura discovered and studied the properties of GFP. Using molecular biological techniques, Chalfie succeeded in introducing the GFP gene into the DNA of the small, almost transparent worm C. elegans, and initiated an era in which GFP would be used as a glowing marker for cellular biology. Finally, Dr.Tsien found precisely how GFP's structure produces the observed green fluorescence, and succeeded in modifying the structure to generate molecules that emit light at slightly different wavelengths, which gave tags of different colors. Fluorescent proteins are very versatile and are being used in many areas, such as microbiology, biotechnology, physiology, environmental engineering, development, etc. They can, for example, illuminate growing cancer tumours; show the development of Alzheimer's disease, or detect arsenic traces in water. Finding the key to how a marine organism produces light unexpectedly ended up providing researchers with a powerful array of tools with which to visualize cell biology in action.
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[
FEBS Lett,
1997]
The discovery of at least 29 genes encoding putative guanylyl cyclases in Caenorhabditis elegans has raised the question as to whether there are numerous receptors yet to be discovered in the mammal. The nematode, however, not only seems ideal to study guanylyl cyclase receptor localization and function, given the large variety of isoforms, but also leads to possible identification of ligands for orphan guanylyl cyclases by the use of genetic and behavioral assays. A recent powerful approach to describe the function of different guanylyl cyclase isoforms in mammals has been the disruption of the corresponding genes in the mouse. A salt resistant elevation of blood pressure, which corresponds to the phenotype of 50% of all human patients with essential hypertension, is observed in mice lacking the GC-A-receptor. Mice missing the GC-C receptor have been shown to be resistant to STa, an E. coli heat-stable enterotoxin, which is largely responsible for travellers diarrhea in adults and mortality due to diarrhea in infants.
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Mol Cell Endocrinol,
2011]
Nuclear hormone receptors (NHRs) are proteins that regulate gene expression in response to developmental, environmental, and nutritional signals. The activity of some NHRs is selectively and reversibly modulated by small molecular weight compounds. However, for others - termed "orphan" receptors - no such ligands have (yet) been identified, and at least some NHRs may lack natural ligands. NHRs exhibit a stereotyped architecture, with conserved N-terminal DNA-binding domains (DBDs) and more variable C-terminal ligand-binding domains (LBDs). NHRs control the transcription of remarkably diverse and specific gene networks, apparently by integrating multiple regulatory inputs that interact with distinct receptor surfaces; these inputs include small molecule ligands, transcriptional coregulators, and response elements, the genomic sites to which the receptors bind. NHRs comprise an ancient superfamily found in all metazoans, and recent findings have revealed NHR-like regulatory factors in fungi. Here, we consider NHR function and evolution in nematodes, roundworms that inhabit terrestrial, marine, and freshwater habitats; we focus in particular on the well-established experimental organism Caenorhabditis elegans. Interestingly, the C. elegans genome encodes a massively expanded NHR family; we speculate that some of the multiple physiological activities governed by individual mammalian NHRs may be distributed among multiple members of the C. elegans family, potentially focusing and simplifying functional analyses. Accordingly, investigations of relevant NHR cofactors, ligands, and response elements might also prove to be simpler; moreover, the abbreviated intergenic regions of the C. elegans genome will facilitate the assignment of response elements to target genes. Finally, the growing interest in medically relevant nematodes is providing novel insights into the function and evolution of NHRs.