Notch Signaling-Induced Oscillatory Gene Expression May Drive Neurogenesis in the Developing Retina.

After integrating classic and cutting-edge research, we proposed a unified model that attempts to explain the key steps of mammalian retinal neurogenesis. We proposed that the Notch signaling-induced lateral inhibition mechanism promotes oscillatory expression of Hes1. Oscillating Hes1 inhibitory activity as a result leads to oscillatory expression of Notch signaling inhibitors, activators/inhibitors of retinal neuronal phenotypes, and cell cycle-promoting genes all within a retinal progenitor cell (RPC). We provided a mechanism explaining not only how oscillatory expression prevents the progenitor-to-precursor transition, but also how this transition happens. Our proposal of the mechanism posits that the levels of the above factors not only oscillate but also rise (with the exception of Hes1) as the factors accumulate within a progenitor. Depending on which factors accumulate fastest and reach the required supra-threshold levels (cell cycle activators or Notch signaling inhibitors), the progenitor either proliferates or begins to differentiate without any further proliferation when Notch signaling ceases. Thus, oscillatory gene expression may regulate an RPC's decision to proliferate or differentiate. Meanwhile, a post-mitotic precursor's selection of one retinal neuronal phenotype over many others depends on the expression level of key transcription factors (activators) required for each of these retinal neuronal phenotypes. Because the events described above are stochastic due to oscillatory gene expression and gene product inheritance from a mother RPC after its division, an RPC or precursor's decision requires the assignment of probabilities to specific outcomes in the selection process. While low and sustained (non-oscillatory) Notch signaling activity is required to promote the transition of retinal progenitors into various retinal neuronal phenotypes, we propose that the lateral inhibition mechanism, combined with high expression of the BMP signaling-induced Inhibitor of Differentiation (ID) protein family, promotes high and sustained (non-oscillatory) Hes1 and Hes5 expression. These events facilitate the transition of an RPC into the Müller glia (MG) phenotype at the late stage of retinal development.