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A Comprehensive in silico Model
of Retinal Neurogenesis

by
Jean-Paul J. Abboud
B.S., 2002
Rutgers, the State University


Thesis Advisor: Richard S. Nowakowski, PhD

Graduate Program: Biomedical Engineering

RWJMS Research Tower
Room V-10
Piscataway

Friday, June 19, 2009
10:00 am


Abstract

The retina is a self-contained outgrowth of the neural tube. Within the developing retina the only proliferative zone, the ventricular zone, produces all 7 retinal cell types (6 neuronal, 1 glial). In the mouse, the full complement of cells is produced over ~22 cell cycles in a specific order from embryonic day 10 until postnatal day 11. This thesis project proposes a biologically realistic model of this cell production process based on the concept that neurogenesis is generally the result of the 3 independent decisions made by each progenitor cell: 1) cell cycle exit decision, 2) cell fate decision, and 3) cell death decision. While each decisional step has been studied independently, this is the first generalized model incorporating all 3 developmental steps to be constructed for any CNS structure. This present work proposes a comprehensive in silico model of mouse retinal neurogenesis that accounts for both cell number and cell class. The in silico model itself has 3 steps: Step 1 reflects the systematic changes in the proportion of daughter cells that remain vs. those that quit the cell cycle. Step 2 reflects a set of probability density functions that describe the cell fate per cell cycle for each of the retinal cell classes. Step 3 reflects the effect of apoptosis on overall cell survival. The model makes allowances for biological processes, such as the natural variations in the types of cell division (symmetric vs. asymmetric), the expansion of the cell population (~150), and proper retinal cell class distributions. The model can simulate the diversity of developmental processes in retinal neurogenesis in central vs. peripheral retina and in different species. Mouse knockouts are exploited to evaluate the biological realism of the model and to evaluate the biological functions of genes involved in retinal development.


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