Nuclear Receptors

Translating Hormone Cues Tissue-Specifically

Science Signaling  07 Apr 2009:
Vol. 2, Issue 65, pp. ec120
DOI: 10.1126/scisignal.265ec120

In insects and nematodes, global hormone signals coordinate tissue-specific morphological and physiological changes to affect developmental transitions such as progression from one larval stage to another. In the nematode Caenorhabditis elegans, mutations in genes encoding microRNAs (miRNAs) often yield heterochronic phenotypes in which the developmental progression of specific tissues fails. In the absence of the steroid hormone Δ4-DA (dafachronic acid), animals enter diapause at the third larval stage (L3), but in the absence of the Δ4-DA receptor DAF-12, animals show heterochronic phenotype in which there are extra hypodermal seam cells, specialized epithelial cells that exhibit stage-specific patterns of proliferation, due to repetition of the L1 cell division program during L2. Because animals lacking the three let-7 miRNA family members mir-48, mir-241, and mir-84 show a phenotype similar to that of the daf-12 null mutants, Bethke et al. tested whether these miRNAs were targets of DAF-12 transcriptional regulation. Through genetics experiments, reporter expression, and gel mobility shift assays, the authors demonstrated that unliganded DAF-12 bound to these promoters to repress their transcription in all tissues during developmental arrest, whereas liganded DAF-12 bound to and activated the promoters of mir-241 and mir-84 in distinct subsets of tissues where they were required to repress the previous developmental program. Thus, nuclear hormone receptor signaling stimulated developmental progression by activating tissue-specific expression of miRNAs that repressed earlier programs.

A. Bethke, N. Fielenbach, Z. Wang, D. J. Mangelsdorf, A. Antebi, Nuclear hormone receptor regulation of microRNAs controls developmental progression. Science 324, 95–98 (2009). [Abstract] [Full Text]