Gene Regulatory Mechanisms Underlying the Spatial and Temporal Regulation of Target-Dependent Gene Expression in XXXX Neurons.

@entity11453 @entity63063 @entity238 @entity71592
UNASSIGNED: Neuronal differentiation often requires target-derived signals from the cells they innervate. These signals typically activate neural subtype-specific genes, but the gene regulatory mechanisms remain largely unknown. Highly restricted expression of the @entity71592 neuropeptide in @entity238 Tv4 neurons requires target-derived @entity11453 signaling and a transcription factor code that includes Apterous. Using integrase transgenesis of enhancer reporters, we functionally dissected the Tv4-enhancer of @entity71592 within its native cellular context. We identified two essential but discrete cis-elements, a @entity11453 -response element ( @entity11453 -RE) that binds @entity11453 -activated pMad, and a homeodomain-response element (HD-RE) that binds Apterous. These cis-elements have low activity and must be combined for Tv4-enhancer activity. Such combinatorial activity is often a mechanism for restricting expression to the intersection of cis-element spatiotemporal activities. However, concatemers of the HD-RE and @entity11453 -RE cis-elements were found to independently generate the same spatiotemporal expression as the Tv4-enhancer. Thus, the Tv4-enhancer atypically combines two low-activity cis-elements that confer the same output from distinct inputs. The activation of target-dependent genes is assumed to 'wait' for target contact. We tested this directly, and unexpectedly found that premature @entity11453 activity could not induce early @entity71592 expression; also, we show that the @entity11453 -insensitive HD-RE cis-element is activated at the time of target contact. This led us to uncover a role for the nuclear receptor, @entity63063 ( @entity63063 ), as a repressor of @entity71592 induction prior to target contact. @entity63063 is normally downregulated immediately prior to target contact, and we found that maintaining @entity63063 expression prevents cis-element activation, whereas reducing @entity63063 gene dosage prematurely activates cis-element activity. We conclude that the target-dependent @entity71592 gene is repressed prior to target contact, and that target-derived @entity11453 signaling directly activates @entity71592 gene expression through an atypical gene regulatory mechanism.
