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Tiffany Cook, Baotong Xie; A conserved OTX-NRL network intersects with the Hippo signaling pathway to control robust photoreceptor fate decisions in the Drosophila eye. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3736.
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Achieving unambiguous cell identity is critical in sensory system development, as the exclusive expression of a single sensory receptor per cell is essential for providing non-overlapping inputs to the brain. In this study, we define a complex, hierarchical regulatory circuit that controls the robust differentiation of blue- vs. green-sensitive photoreceptors (PRs) in the Drosophila compound eye. Previous studies showed that this cell fate decision requires a bistable negative feedback loop between two signaling proteins: the Melted pleckstrin homology-domain protein in blue PRs and Lats, the key effector kinase in the Hippo tumor suppressor pathway in green PRs. How these two signaling proteins lead to changes in gene expression and ultimately effect cell fate in post-mitotic neurons, however, is not known.
Using a combination of genetic-based screening, epistasis studies, promoter mapping, and transcriptional regulatory assays, we define a cascade of transcriptional regulatory factors that intersect with the Melted-Lats bistable loop that are neceesary for blue vs green PR fate decisions.
We find that a hierarchical transcriptional network functions upstream, within, and downstream of the Melted-Lats bistable loop to promote blue- and repress green- photoreceptor fate. This network includes a conserved feedforward loop between OTX and NRL-related transcription factors that intersect within an unexpected multi-level feedback circuit involving Lats, the Yorkie/YAP transcriptional co-activator and the TEA-related transcription factor Scalloped.
Integration and re-implementation of the same regulatory modules guarantee unambiguous fate decisions, thus regulating both cell fate determinants and terminal differentiation genes. Together, our study demonstrates that a conserved OTX/NRL cascade integrates with the Hippo tumor suppressor pathway to ensure robust and stable PR fate decisions. These studies not only lend insight into how post-mitotic neurons achieve an unambiguous cell fate, but also provide mechanistic insight into how OTX and NRL-related MAF factors may regulate cell growth in other developmental and pathological processes.
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