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Mammalian retinal development
The mammalian retina is made up of seven classes of cell types (rod, cone, horizontal, amacrine, bipolar, ganglion, and Müller cells) that can be further subdivided into 55-60 functionally distinct subtypes (Jeon et al., 1998; MacNeil & Masland, 1998; MacNeil et al., 1999). Lineage studies have demonstrated that during development, each of these distinct cell types is generated from multipotent retinal progenitor cells in an evolutionarily conserved birth order (Fig. 1) (Turner & Cepko, 1987; Turner et al., 1990). Cepko proposed that multipotent retinal progenitor cells undergo unidirectional transitions in competence to generate each retinal cell type in the proper birth order (Fig. 1) (Cepko et al., 1996). For example, early-stage retinal progenitor cells are competent to give rise to early-born cell types such as ganglion cells, and late-stage retinal progenitor cells are competent to give rise to late-born cell types such as bipolar cells (Fig. 1). In addition to intrinsically changing retinal progenitor cell competence, the microenvironment of the developing retina also influences retinogenesis (Belliveau & Cepko, 1999; Belliveau et al., 2000; Wang et al., 2002; Dakubo et al., 2003; Young & Cepko, 2004). Not only must retinal progenitor cell competence be precisely coordinated with the changing microenvironment, but also it must be coordinated with the decision to exit the cell cycle (Dyer & Cepko, 2001; Dyer, 2003; Donovan & Dyer, 2005; Dyer & Bremner, 2005). For example, if too many retinal progenitor cells exit the cell cycle during the early stages of retinal development, there may be an increase in early-born cell types at the expense of late-born cell types and vice versa . Intrinsic programs in retinal progenitor cells as well as extrinsic cues most likely regulate cell cycle exit. When proliferation is deregulated during development, not only will the ratio of retinal cell types be altered, but also blindness may result from degeneration (Ma et al., 1998), retinal dysplasia (Dyer & Cepko, 2000), or retinoblastoma (Dyer, 2004; Zhang et al., 2004a ,b ; Dyer & Bremner, 2005).
Temporal and spatial heterogeneity of developing retinal progenitor cells. Retinal formation spans approximately 2 weeks in the developing mouse and several months in the developing human. During this time, retinal progenitor cells divide and generate postmitotic cells that commit...