Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation

Shuying He, Saima Limi, Rebecca S. McGreal, Qing Xie, Lisa A. Brennan, Wanda Lee Kantorow, Juraj Kokavec, Romit Majumdar, Harry Hou, Winfried Edelmann, Wei Liu, Ruth Ashery-Padan, Jiri Zavadil, Marc Kantorow, Arthur I. Skoultchi, Tomas Stopka, Ales Cvekl

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Ocular lensmorphogenesis is a model for investigatingmechanisms 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 Snf2hflox 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, p27Kip1 (Cdkn1b) and p57Kip2 (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.

Original languageEnglish (US)
Pages (from-to)1937-1947
Number of pages11
JournalDevelopment (Cambridge)
Volume143
Issue number11
DOIs
StatePublished - Jun 1 2016

Keywords

  • Brg1
  • Cataract
  • Denucleation
  • Lens
  • Smarca4
  • Smarca5
  • Snf2h
  • Terminal differentiation

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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    He, S., Limi, S., McGreal, R. S., Xie, Q., Brennan, L. A., Kantorow, W. L., Kokavec, J., Majumdar, R., Hou, H., Edelmann, W., Liu, W., Ashery-Padan, R., Zavadil, J., Kantorow, M., Skoultchi, A. I., Stopka, T., & Cvekl, A. (2016). Chromatin remodeling enzyme Snf2h regulates embryonic lens differentiation and denucleation. Development (Cambridge), 143(11), 1937-1947. https://doi.org/10.1242/dev.135285