title: Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation.
abstract: Ocular lens morphogenesis is a model for investigating mechanisms of cellular differentiation, spatial and temporal gene expression control, and chromatin regulation. Brg1 (Smarca4) and Snf2h (Smarca5) are catalytic subunits of distinct ATP-dependent chromatin remodeling complexes implicated in transcriptional regulation. Previous studies have shown that Brg1 regulates both lens fiber cell differentiation and organized degradation of their nuclei (denucleation). Here, we employed a conditional Snf2h(flox) mouse model to probe the cellular and molecular mechanisms of lens formation. Depletion of Snf2h induces premature and expanded differentiation of lens precursor cells forming the lens vesicle, implicating Snf2h as a key regulator of lens vesicle polarity through spatial control of Prox1, Jag1, p27(Kip1) (Cdkn1b) and p57(Kip2) (Cdkn1c) gene expression. The abnormal Snf2h(-/-) fiber cells also retain their nuclei. RNA profiling of Snf2h(-/) (-) and Brg1(-/-) eyes revealed differences in multiple transcripts, including prominent downregulation of those encoding Hsf4 and DNase IIβ, which are implicated in the denucleation process. In summary, our data suggest that Snf2h is essential for the establishment of lens vesicle polarity, partitioning of prospective lens epithelial and fiber cell compartments, lens fiber cell differentiation, and lens fiber cell nuclear degradation.
authors.affiliation: Department of Ophthalmology & Visual Sciences and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Shuying
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Ophthalmology & Visual Sciences and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Saima
authors.initials: S
authors.lastname: Limi
authors.affiliation: Department of Ophthalmology & Visual Sciences and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: McGreal
authors.affiliation: Department of Ophthalmology & Visual Sciences and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Biomedical Science, Florida Atlantic University, Boca Raton, FL 33431, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Brennan
authors.affiliation: Department of Biomedical Science, Florida Atlantic University, Boca Raton, FL 33431, USA.
authors.forename: Wanda Lee
authors.initials: WL
authors.lastname: Kantorow
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA First Faculty of Medicine, Charles University, 121 08 Prague, Czech Republic.
authors.forename: Juraj
authors.initials: J
authors.lastname: Kokavec
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Romit
authors.initials: R
authors.lastname: Majumdar
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Hou
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.affiliation: Department of Ophthalmology & Visual Sciences and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine Tel-Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ashery-Padan
authors.affiliation: Department of Pathology and NYU Center for Health Informatics and Bioinformatics, New York University Langone Medical Center, New York, NY 10016, USA Mechanisms of Carcinogenesis Section, International Agency for Research on Cancer, Lyon Cedex 08 69372, France.
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.affiliation: Department of Biomedical Science, Florida Atlantic University, Boca Raton, FL 33431, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Kantorow
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Skoultchi
authors.affiliation: First Faculty of Medicine, Charles University, 121 08 Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Stopka
authors.affiliation: Department of Ophthalmology & Visual Sciences and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA ales.cvekl@einstein.yu.edu.
authors.forename: Ales
authors.identifier: 0000-0002-3957-789X
authors.initials: A
authors.lastname: Cvekl
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D002451:Cell Compartmentation; D002453:Cell Cycle; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D000076249:Heat Shock Transcription Factors; D007908:Lens, Crystalline / Q000166:cytology* / Q000196:embryology*; D018345:Mice, Knockout; D063306:Mitophagy; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D000071841:PAX6 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; C484462:Hsf4 protein, mouse; D009687:Nuclear Proteins; D000071841:PAX6 Transcription Factor; C000605732:Pax6 protein, mouse; D014157:Transcription Factors; D000251:Adenosine Triphosphatases; C513194:Smarca4 protein, mouse; C498725:Smarca5 protein, mouse; D004265:DNA Helicases
keywords: Brg1; Cataract; Denucleation; Lens; Smarca4; Smarca5; Snf2h; Terminal differentiation