How differential levels of gene expression are controlled in post-mitotic neurons is poorly understood. In the Drosophila retina, expression of the transcription factor Defective Proventriculus (Dve) at distinct cell type-specific levels is required for terminal differentiation of color- and motion-detecting photoreceptors. Here, we find that the activities of two cis-regulatory enhancers are coordinated to drive dve expression in the fly eye. Three transcription factors act on these enhancers to determine cell-type specificity. Negative autoregulation by Dve maintains expression from each enhancer at distinct homeostatic levels. One enhancer acts as an inducible backup (‘dark’ shadow enhancer) that is normally repressed but becomes active in the absence of the other enhancer. Thus, two enhancers integrate combinatorial transcription factor input, feedback and redundancy to generate cell type-specific levels of dve expression and stable photoreceptor fate. This regulatory logic may represent a general paradigm for how precise levels of gene expression are established and maintained in post-mitotic neurons.
Author contributions
Conceptualization: J.Y., G.G., R.J.J.; Methodology: J.Y., S.T., G.G., R.J.J.; Investigation: J.Y., C.A., K.V., S.T., G.G.; Writing – original draft: J.Y., R.J.J.; Writing – review and editing: J.Y., R.J.J., S.S.; Funding acquisition: S.S., R.J.J.; Supervision: R.J.J.
Funding
R.J.J. and S.S. were supported by the National Institute of General Medical Sciences (R01GM106090-01A1/NYU F7784-01). R.J.J. was supported by a Pew Scholar Award from Pew Charitable Trusts (00027373), by a March of Dimes Foundation Basil O'Connor Scholar Award (5-FY15-21) and by the National Eye Institute (R01EY025598). Deposited in PMC for release after 12 months.
