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 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.
Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, 1 Tower Road, Ithaca, New York 14853 (USA) http://bti.cornell.edu/schroeder.
Joshua C
JC
Judkins
Parag
P
Mahanti
Jacob B
JB
Hoffman
Isaiah
I
Yim
Adam
A
Antebi
Frank C
FC
Schroeder
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002635:Chenodeoxycholic Acid / Q000737:chemistry; D007814:Larva / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008095:Lithocholic Acid / Q000737:chemistry; D010782:Photolysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology; D014466:Ultraviolet Rays
D000577:Amides; D029742:Caenorhabditis elegans Proteins; C410905:DAF-12 protein, C elegans; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids; D002635:Chenodeoxycholic Acid; D008095:Lithocholic Acid
amides; gene expression; photolysis; small-molecule signaling; steroid hormones