A new paper in Development revisits a classic model system of developmental biology – photoreceptor cell fate specification in the Drosophila eye – and introduces a quantitative systems-level analysis of cell lineage restriction from multipotency. It reports that cell state transitions to photoreceptor fates are driven by unexpectedly modest two-fold changes in the stoichiometric ratio of two ETS-domain transcription factors called Yan and Pnt. By following Pnt and Yan protein expression dynamics concurrently at the single-cell level across hundreds of cell state transitions, the team discovered that the ratio of the two factors remains remarkably constant. Only when cells transition from progenitor to photoreceptor states does the ratio change – rapidly increasing two-fold in response to Ras/ERK signals.
Genetic manipulations that perturb the ratio cause progenitor cells to either prematurely transit or fail to transit to photoreceptor fates, implicating the Pnt/Yan ratio as the driver of these transitions. Using a biophysical model, the team shows how modest two-fold changes in the Pnt/Yan ratio will cause large changes in relative DNA occupancy by Yan and Pnt to alter target gene transcription.
In addition to revising a long-standing model in developmental biology, the work uncovers a novel regulatory mechanism that might confer robustness and ultra sensitivity to many kinds of biological transitions.
