TY - JOUR
T1 - Notch Signaling-Induced Oscillatory Gene Expression May Drive Neurogenesis in the Developing Retina
AU - Ivanov, Dmitry
N1 - Funding Information:
The author thanks Dr. Daniel Pelaez and Dr. Steve Pappas for advice and insightful discussions. The author is also grateful to Dr. Steve Pappas for critically reading an early version of this manuscript. The author thankfully acknowledges the thoughtful and critical suggestions on this manuscript by Dr. Galina Dvoriantchikova, Rajeev J. Seemungal, Xenia Dvoriantchikova. Funding. Supported in part by the National Institutes of Health/National Eye Institutes Grant R01 EY027311 (DI), National Institutes of Health Center Core Grant P30EY014801, Research to Prevent Blindness Unrestricted Grant, Incorporation (New York, NY, USA).
PY - 2019/9/19
Y1 - 2019/9/19
N2 - 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.
AB - 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.
KW - lateral inhibition
KW - notch signaling
KW - oscillatory gene expression
KW - retinal neurogenesis
KW - retinal phenotypes
KW - retinal progenitor cells
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U2 - 10.3389/fnmol.2019.00226
DO - 10.3389/fnmol.2019.00226
M3 - Article
AN - SCOPUS:85072991541
VL - 12
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
SN - 1662-5099
M1 - 226
ER -