The tailless nuclear receptor acts as a dedicated repressor in the early Drosophila embryo.

Tailless is an orphan nuclear receptor that controls terminal body patterning in Drosophila. Genetic analyses have revealed both positive and negative regulatory interactions of Tailless with various target genes, leading to the idea that, like many other nuclear receptors, Tailless mediates both activation and repression of transcription. In this paper, we have examined the consequences of converting Tailless into an obligate repressor and compared the activities of the resulting protein with those of wild-type Tailless. We find that this repressor form of Tailless behaves like the intact protein in gain- and loss-of-function experiments, being sufficient to support normal embryonic development and establish accurate patterns of gene expression even for positive Tailless targets such as hunchback and brachyenteron. This suggests that Tailless functions exclusively as a transcriptional repressor in the embryo and that the observed positive interactions of Tailless with specific targets are secondary effects involving repression of repressors. We provide evidence that knirps is one such repressor gene acting between Tailless and its indirect positive targets. Finally, our results indicate that Tailless exerts an active mechanism of repression via its ligand-binding domain and that this activity is largely independent of the activation function 2 (AF2) motif characteristic of most nuclear receptors.