High-throughput three-dimensional characterization of the developing vertebrate retina

The balance between self-renewal and terminal differentiation of neural progenitors is regulated by a complex interplay of signaling pathways that set the spatial and temporal cues that ultimately shape and organize neurogenic tissues. The developing vertebrate retina is a widely used model to study how these key signaling cascades modulate the mode and rate of division of neural progenitors. In this contribution, we combine in toto experiments with three-dimensional image analysis, computational modeling, and theoretical tools to provide a quantitative characterization of the dynamics of growth and differentiation of the developing vertebrate retina. We show that the tissue develops by gradually increasing the average rate of differentiation and reducing the average cell cycle length. Moreover, this balance between differentiation with cell cycle duration increases the yield of production of terminally differentiated neurons, and it is required to achieve a well-defined exponential growth. We also show that a potential regulator of this balance is Hedgehog (Hh), promoting simultaneously cell cycle progression and cell cycle exit of RPCs. Our results represent a detailed and accurate quantitative characterization of retinal neurogenesis and how signals regulate the balance between proliferation and differentiation during the development of the vertebrate retina. Significance StatementThe precise differentiation of neural progenitors during development ensures the correct cognitive, sensory, and motor functions of higher organisms. In this contribution, we characterize with quantitative precision the dynamics of growth and differentiation of the zebrafish developing retina during the first wave of neurogenic differentiation, using a combination of experimental/theoretical and computational tools. Our analysis reveals a progressive shift from proliferative to differentiative divisions, which correlates with cell cycle acceleration. Using small-molecule inhibition, we show that Hedgehog (Hh) signaling promotes both cell cycle exit and cell cycle progression, a balance required for well-defined exponential growth of the tissue.