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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 FMRFa neuropeptide in  Drosophila  Tv4 neurons requires target-derived BMP signaling and a transcription factor code that includes Apterous. Using integrase transgenesis of enhancer reporters, we functionally dissected the Tv4-enhancer of  FMRFa  within its native cellular context. We identified two essential but discrete  cis -elements, a BMP-response element (BMP-RE) that binds BMP-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 BMP-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 BMP activity could not induce early  FMRFa  expression; also, we show that the BMP-insensitive HD-RE  cis -element is activated at the time of target contact. This led us to uncover a role for the nuclear receptor,  seven up (svp) , as a repressor of  FMRFa  induction prior to target contact. Svp is normally downregulated immediately prior to target contact, and we found that maintaining Svp expression prevents  cis -element activation, whereas reducing  svp  gene dosage prematurely activates  cis -element activity. We conclude that the target-dependent  FMRFa  gene is repressed prior to target contact, and that target-derived BMP signaling directly activates  FMRFa  gene expression through an atypical gene regulatory mechanism.

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