During retinal development, neuroepithelial progenitor cells switch from a symmetric proliferative mode, where both daughter cells remain in the mitotic cycle, to a neurogenic mode, where at least one of the daughter cells exits the cell cycle and differentiates as a neuron (or later as a glial cell). The cellular mechanisms that promote neurogenic divisions in the vertebrate nervous system remain unknown. Several recent observations demonstrate a fundamental role for interkinetic nuclear migration (IKNM) and polarized signals in regulating neurogenesis within the retina. IKNM is the process in which neuroepithelial nuclei oscillate from the apical to basal surface in phase with the mitotic cycle. We will investigate how specific phases of the cell cycle and the apical-basal position of the nucleus in progenitor cells impact the selection of neurogenic cell divisions and ultimately facilitate normal retinal lamination. In our studies, we will also investigate the influence of polarized signals during retinogenesis. This research will provide fundamental insights into signal integration and cell-fate commitment of retinal progenitor cells. Because of the fundamental nature of this research, our results have relevance to both retinal stem cell manipulation and disease processes.

Public Health Relevance

This proposal outlines experiments to understand the mechanisms for how progenitor cells are selected to generate neurons. Fundamental knowledge of this process is important for guiding further research on stem cell biology, regenerative medicine, and retinal disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Greenwell, Thomas
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Medical College of Wisconsin
Anatomy/Cell Biology
Schools of Medicine
United States
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Lewis, Tylor R; Kundinger, Sean R; Link, Brian A et al. (2018) Kif17 phosphorylation regulates photoreceptor outer segment turnover. BMC Cell Biol 19:25
Lewis, Tylor R; Zareba, Mariusz; Link, Brian A et al. (2018) Cone myoid elongation involves unidirectional microtubule movement mediated by dynein-1. Mol Biol Cell 29:180-190
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Porazinski, Sean; Wang, Huijia; Asaoka, Yoichi et al. (2015) YAP is essential for tissue tension to ensure vertebrate 3D body shape. Nature 521:217-221
Miesfeld, Joel B; Link, Brian A (2014) Establishment of transgenic lines to monitor and manipulate Yap/Taz-Tead activity in zebrafish reveals both evolutionarily conserved and divergent functions of the Hippo pathway. Mech Dev 133:177-88
Paulus, Jeremiah D; Link, Brian A (2014) Loss of optineurin in vivo results in elevated cell death and alters axonal trafficking dynamics. PLoS One 9:e109922
Tang, Yujie; Gholamin, Sharareh; Schubert, Simone et al. (2014) Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med 20:732-40
Clark, Brian S; Cui, Shuang; Miesfeld, Joel B et al. (2012) Loss of Llgl1 in retinal neuroepithelia reveals links between apical domain size, Notch activity and neurogenesis. Development 139:1599-610

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