SWI/SNF chromatin remodeling ATPase Brm regulates the differentiation of early retinal stem cells/progenitors by influencing Brn3b expression and Notch signaling.
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.
Das
Ani V
AV
Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
James
Jackson
J
Bhattacharya
Sumitra
S
Imbalzano
Anthony N
AN
Antony
Marie Lue
ML
Hegde
Ganapati
G
Zhao
Xing
X
Mallya
Kavita
K
Ahmad
Faraz
F
Knudsen
Eric
E
Ahmad
Iqbal
I
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000502:physiology*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D004265:DNA Helicases; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D008954:Models, Biological; D009687:Nuclear Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D051881:Receptor, Notch1 / Q000096:biosynthesis*; D012160:Retina / Q000166:cytology / Q000196:embryology*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D050820:Transcription Factor Brn-3B / Q000096:biosynthesis*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D018797:Cell Cycle Proteins; D002843:Chromatin; C497763:Notch1 protein, rat; D009687:Nuclear Proteins; C509835:Pou4f2 protein, rat; D051881:Receptor, Notch1; D050820:Transcription Factor Brn-3B; D014157:Transcription Factors; D000251:Adenosine Triphosphatases; C578929:Smarca4 protein, rat; D004265:DNA Helicases