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.
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.
|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|
|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|
|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|
|Willardsen, Minde I; Link, Brian A (2011) Cell biological regulation of division fate in vertebrate neuroepithelial cells. Dev Dyn 240:1865-79|
|Clark, Brian S; Winter, Mark; Cohen, Andrew R et al. (2011) Generation of Rab-based transgenic lines for in vivo studies of endosome biology in zebrafish. Dev Dyn 240:2452-65|
|Bachmann-Gagescu, Ruxandra; Phelps, Ian G; Stearns, George et al. (2011) The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking. Hum Mol Genet 20:4041-55|
|Insinna, Christine; Baye, Lisa M; Amsterdam, Adam et al. (2010) Analysis of a zebrafish dync1h1 mutant reveals multiple functions for cytoplasmic dynein 1 during retinal photoreceptor development. Neural Dev 5:12|
|Choi, Jung-Hwan; Law, Mei-Yee; Chien, Chi-Bin et al. (2010) In vivo development of dendritic orientation in wild-type and mislocalized retinal ganglion cells. Neural Dev 5:29|
|Hava, David; Forster, Ulrike; Matsuda, Miho et al. (2009) Apical membrane maturation and cellular rosette formation during morphogenesis of the zebrafish lateral line. J Cell Sci 122:687-95|
|Baye, Lisa M; Link, Brian A (2008) Nuclear migration during retinal development. Brain Res 1192:29-36|
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