Chromatin remodeling enzyme Snf2h is essential for retinal cell proliferation and photoreceptor maintenance

Abstract

AbstractChromatin remodeling complexes are required for many distinct nuclear processes such as transcription, DNA replication and DNA repair. However, how these complexes contribute to the development of complex tissues within an organism is poorly characterized. Imitation switch (ISWI) proteins are among the most evolutionarily conserved ATP-dependent chromatin remodeling factors and are represented by yeast Isw1/Isw2, and their vertebrate counterparts Snf2h (Smarca5) and Snf2l (Smarca1). In this study, we focused on the role of theSnf2hgene during development of the mammalian retina. We show thatSnf2his expressed in both retinal progenitors and post-mitotic retinal cells. UsingSnf2hconditional knockout mice (Snf2hcKO), we found that whenSnf2his deleted the laminar structure of the adult retina is not retained, the overall thickness of the retina is significantly reduced compared with controls, and the outer nuclear layer (ONL) is completely missing. Depletion of Snf2h did not influence the ability of retinal progenitors to generate all of the differentiated retinal cell types. Instead, Snf2h function is critical for proliferation of retinal progenitor cells. Cells lacking Snf2h have a defective S-phase, leading to the entire cell division process impairments. Although, all retinal cell types appear to be specified in the absence of Snf2h function, cell cycle defects and concomitantly increased apoptosis inSnf2hcKO result in abnormal retina lamination, complete destruction of the photoreceptor layer and, consequently, in a physiologically non-functional retina.