Cell cycle mediated regulation of retinal development: insights from D-Cyclin knockout mice

During nervous system development, progenitor cells multiply under the control of the cell cycle pathway. When they are poised to differentiate, they withdraw from the cell cycle to form appropriate neuronal cell types. Cell cycle regulation is therefore closely intertwined with progenitor proliferation and neurogenesis in the developing nervous system and often, common factors and pathways are utilized in these processes. Two properties of neuronal progenitors can be critical for proper nervous system development: the time they take to complete one cell cycle, and the exact timing of their withdrawal/exit from the cell cycle to form neurons. Understanding how these properties can be manipulated to influence progenitor cell proliferation and neurogenesis can be invaluable for devising therapeutic strategies involving neuronal stem/progenitor cells. Retina, the primary tissue for vision, is an excellent model system for studying nervous system development and neuronal progenitor cell biology. To gain potential insights into the issues described above, this dissertation focuses on the role of the cell cycle regulators the D-cyclins, Cyclin D1 (Ccnd1) and Cyclin D3 (Ccnd3), during retinal development and characterizes the retinal phenotypes of Ccnd1 and Ccnd3 knockout mice. Chapter 1 is an introduction to retinal development and sets up the relevant questions addressed here. Chapter 2 is a reprint of a published journal article titled, "Cyclin D1 fine-tunes iv the neurogenic output of embryonic retinal progenitor cells." The study shows that during mouse embryonic development, CCND1 expression in retinal progenitor cells (RPCs) is critical for maintenance of their cell cycle time and also for their timing of exit from the cell cycle. Further, CCND1 ensures that the correct complements of early-born retinal neurons are generated from progenitors. Chapter 3 deals with the role of D-cyclins during postnatal retina development. The study shows that CCND1 also influences the production rate of late-born retinal cell types. Unexpectedly, although Ccnd1 null retinas experience progenitor cell depletion during development, proliferation, and neurogenesis persist well beyond the normal period of retinal histogenesis in mutant retinas. Further, Ccnd3 is unable to compensate for Ccnd1's role in regulation of cell cycle time and cell cycle withdrawal. Chapter 4 discusses the implications and relevance of the above studies. Future directions for these studies are also outlined.