A Photocleavable Masked Nuclear-Receptor Ligand Enables Temporal Control of C.elegans Development

The development and lifespan of C.elegans are controlled by the nuclear hormone receptor DAF-12, an important model for the vertebrate vitaminD and liverX receptors. As with its mammalian homologues, DAF-12 function is regulated by bile acid-like steroidal ligands; however, tools for investigating t...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2014-02, Vol.53 (8), p.2110-2113
Main Authors: Judkins, Joshua C, Mahanti, Parag, Hoffman, Jacob B, Yim, Isaiah, Antebi, Adam, Schroeder, Frank C
Format: Article
Language:English
Subjects:
Amides
Homology
Ligands
Masking
Mathematical models
Receptors
Temporal logic
Worms
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Summary:The development and lifespan of C.elegans are controlled by the nuclear hormone receptor DAF-12, an important model for the vertebrate vitaminD and liverX receptors. As with its mammalian homologues, DAF-12 function is regulated by bile acid-like steroidal ligands; however, tools for investigating their biosynthesis and function invivo are lacking. A flexible synthesis for DAF-12 ligands and masked ligand derivatives that enable precise temporal control of DAF-12 function was developed. For ligand masking, photocleavable amides of 5-methoxy-N-methyl-2-nitroaniline (MMNA) were introduced. MMNA-masked ligands are bioavailable and after incorporation into the worm, brief UV irradiation can be used to trigger the expression of DAF-12 target genes and initiate development from dauer larvae into adults. The invivo release of DAF-12 ligands and other small-molecule signals by using photocleavable MMNA-masked ligands will enable functional studies with precise spatial and temporal resolution. [PUBLICATION ABSTRACT]
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201307465