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J. Biol. Chem., Vol. 282, Issue 48, 35187-35201, November 30, 2007

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SWI/SNF Chromatin Remodeling ATPase Brm Regulates the Differentiation of Early Retinal Stem Cells/Progenitors by Influencing Brn3b Expression and Notch Signaling^*

Ani V. Das, Jackson James, Sumitra Bhattacharya, Anthony N. Imbalzano^¶, Marie Lue Antony, Ganapati Hegde, Xing Zhao, Kavita Mallya, Faraz Ahmad, Eric Knudsen^||, and Iqbal Ahmad¹

From the Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, the Department of Neurobiology, Rajiv Gandhi Center for Biotechnology, Kerala 695014, India, the ^¶Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, and the ^||Department of Cell and Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45267

Based on a variety of approaches, evidence suggests that different cell types in the vertebrate retina are generated by multipotential progenitors in response to interactions between cell intrinsic and cell extrinsic factors. The identity of some of the cellular determinants that mediate such interactions has emerged, shedding light on mechanisms underlying cell differentiation. For example, we know now that Notch signaling mediates the influence of the microenvironment on states of commitment of the progenitors by activating transcriptional repressors. Cell intrinsic factors such as the proneural basic helix-loop-helix and homeodomain transcription factors regulate a network of genes necessary for cell differentiation and maturation. What is missing from this picture is the role of developmental chromatin remodeling in coordinating the expression of disparate classes of genes for the differentiation of retinal progenitors. Here we describe the role of Brm, an ATPase in the SWI/SNF chromatin remodeling complex, in the differentiation of retinal progenitors into retinal ganglion cells. Using the perturbation of expression and function analyses, we demonstrate that Brm promotes retinal ganglion cell differentiation by facilitating the expression and function of a key regulator of retinal ganglion cells, Brn3b, and the inhibition of Notch signaling. In addition, we demonstrate that Brm promotes cell cycle exit during retinal ganglion cell differentiation. Together, our results suggest that Brm represents one of the nexus where diverse information of cell differentiation is integrated during cell differentiation.

Received for publication, August 14, 2007

^* This work was supported by The Lincy Foundation, Pearsons Foundation, Nebraska Tobacco Fund for Biomedical Research, and Research to Prevent Blindness. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Ophthalmology and Visual Sciences, 4044 Durham Research Center, University of Nebraska Medical Center, Omaha, NE 68198-5840. Tel.: 402-559-4091; Fax: 402-559-3251; E-mail: iahmad{at}unmc.edu.

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				S. Flowers, N. G. Nagl Jr., G. R. Beck Jr., and E. Moran Antagonistic Roles for BRM and BRG1 SWI/SNF Complexes in Differentiation J. Biol. Chem., April 10, 2009; 284(15): 10067 - 10075. [Abstract] [Full Text] [PDF]

				S. Bhattacharya, A. V. Das, K. B. Mallya, and I. Ahmad Ciliary Neurotrophic Factor-Mediated Signaling Regulates Neuronal Versus Glial Differentiation of Retinal Stem Cells/Progenitors by Concentration-Dependent Recruitment of Mitogen-Activated Protein Kinase and Janus Kinase-Signal Transducer and Activator of Transcription Pathways in Conjunction with Notch Signaling Stem Cells, October 1, 2008; 26(10): 2611 - 2624. [Abstract] [Full Text] [PDF]