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Title: Interplay between interkinetic nuclear migration and cell fate determination in the developing zebrafish retina
Author: Azizi, Afnan
ISNI:       0000 0004 7962 0439
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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The vertebrate central nervous system (CNS) is arranged into exquisitely organized strata from a diverse collection of neuronal types. The zebrafish retina is a well-established model for studying the vertebrate CNS because it can be readily accessed during development and directly imaged. All main retinal cell types are derived from multipotent retinal progenitor cells (RPCs), whose clonal sizes and compositions are stochastically determined. However, the biological processes that contribute to the stochastic cell fate decision making of RPCs remain largely unexplored. Another major hallmark of neural development is the oscillatory movement of nuclei between the apical and basal surfaces of the neuroepithelium during the process of interkinetic nuclear migration (IKNM). The precise role of IKNM in creating the organized diversity of neuronal tissues is the topic of continued and vigorous investigation. Therefore, we employed long-term, rapid imaging of whole zebrafish retinas during early stages of development to reveal the physical processes that govern the behavior of nuclei during IKNM and their contribution to variability in fate decision making of RPCs. We opti- mized the use of light sheet and two-photon microscopy techniques to image the developing zebrafish retina at a high temporal resolution over long time periods. These images made the raw material for production of reliable tracks of nuclear movements and division during early retinogenesis, for many tightly packed nuclei, using automated tracking software and manual curation. Subsequently, these tracks were used to create a model of retinal IKNM as a diffusive process across a nuclear concentration gradient generated by the addition of new nuclei at the apical surface. This analytical model is based on the observed stochastic basal movements of the nuclei during IKNM and produces a diffusion constant in line with those previously reported in the literature. Therefore, based on crowding of nuclei at the apical surface and a nuclear concentration gradient along the apicobasal axis, it provides a reasonable quantitative explanation for the stochastic distribution of nuclei across the retina. Furthermore, analysis of nuclear migration and cell fate determination imply a significant contribution of nuclear position and time spent near the basal surface on cell fate choices. These results suggest that IKNM may stochastically distribute nuclei across the retina whose positions, in turn, affect their fate choices.
Supervisor: Harris, William Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: zebrafish retina ; interkinetic nuclear migration ; differentiation ; two photon microscopy ; diffusive process