A Photocleavable Masked Nuclear‐Receptor Ligand Enables Temporal Control of <i>C. elegans</i> Development

Abstract

The development and lifespan of C. elegans are controlled by the nuclear hormone receptor DAF-12, an important model for the vertebrate vitamin D and liver X 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 in vivo 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 in vivo 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.