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CIS-regulatory integration of intrinsic transcription factors with target-derived signals in neuronal differentiation Tang, Chung Yiu Jonathan


We now know that expression of the appropriate terminal differentiation gènes (TDG), such as neuropeptides, neurotransmitters, ion channels, etcetera, in maturing neurons is controlled by cell-specific combinations of transcription factors and by signals secreted from the neurons' target cells. However, it is unclear how thèse two regulatory inputs are integrated inside neurons. In Drosophila, target-derived Bone Morphogenetic Protein (BMP) signals and a well-characterized combinatorial code of transcription factors activate expression of the FMRFa gene in the Tv neurons. Here, I performed a cis-regulatory analysis of FMRFa in order to understand how the two factors functionally intersect. Mutant analysis reveals that 4 of the 7 known FMRFa regulators, Apterous, BMP signalling, Dachshund and Zfhl, ail regulate the expression of the Tv enhancer, a 446 bp cw-regulatory element that faithfully reproduces FMRFa expression in the Tv neurons. Within the Tv enhancer, I identified a functional module, termed HD/BRE-A, that is predicted to respond to both BMP signalling and the homeodomain transcription factor Apterous. I also verified that Apterous and the BMP factors, Mad and Medea, can directly bind to HD/BRE-A in vitro. Furthermore, transgenic analyse indicate that the positioning between the Apterous and Medea binding site is critical for Tv enhancer activation, suggesting a strict physical requirement for simultaneous association of these factors. Taken together, my results supports a model of cis-regulatory integration of BMP signaling and homeodomain transcription factors in the regulation of TDGs.

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