Abstract
Retinal development requires precise temporal and spatial coordination of cell cycle exit, cell fate specification, cell migration and differentiation. When this process is disrupted, retinoblastoma, a developmental tumor of the retina, can form. Epigenetic modulators are central to precisely coordinating developmental events, and many epigenetic processes have been implicated in cancer. Studying epigenetic mechanisms in development is challenging because they often regulate multiple cellular processes; therefore, elucidating the primary molecular mechanisms involved can be difficult. Here we explore the role of Brg1 (Smarca4) in retinal development and retinoblastoma in mice using molecular and cellular approaches. Brg1 was found to regulate retinal size by controlling cell cycle length, cell cycle exit and cell survival during development. Brg1 was not required for cell fate specification but was required for photoreceptor differentiation and cell adhesion/polarity programs that contribute to proper retinal lamination during development. The combination of defective cell differentiation and lamination led to retinal degeneration in Brg1-deficient retinae. Despite the hypocellularity, premature cell cycle exit, increased cell death and extended cell cycle length, retinal progenitor cells persisted in Brg1-deficient retinae, making them more susceptible to retinoblastoma. ChIP-Seq analysis suggests that Brg1 might regulate gene expression through multiple mechanisms.
Highlights
Multipotent retinal progenitor cells undergo unidirectional changes in competence during development to produce each of the seven classes of cell types in an evolutionarily conserved birth order (Cepko et al, 1996; Livesey and Cepko, 2001)
To study the mechanism of RB1-mediated epigenetic regulation of cell proliferation, differentiation and survival, we have focused on BRG1 (SMARCA4), which is an ATPase subunit of the SWI/SNF complex involved in nucleosome mobilization during development and tumorigenesis (Dunaief et al, 1994)
Brg1-deficient retinae are hypocellular To explore the role of Brg1 in retinal development, we generated Chx10-Cre;Brg1Lox/Lox mice (Chx10 is known as Vsx2)
Summary
Multipotent retinal progenitor cells undergo unidirectional changes in competence during development to produce each of the seven classes of cell types in an evolutionarily conserved birth order (Cepko et al, 1996; Livesey and Cepko, 2001). Proliferation must be precisely controlled during this process to ensure that each cell type is produced at the correct time during development and in the appropriate proportion (Dyer and Cepko, 2001a). When proliferation and differentiation become uncoupled during retinogenesis, a developmental tumor of the retina called retinoblastoma can form (Dyer and Bremner, 2005). The precise mechanism by which RB1 coordinates these different processes in multipotent retinal progenitor cells is unknown
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