Lens fiber cell differentiation and denucleation are disrupted through expression of the N-terminal nuclear receptor box of NCOA6 and result in p53-dependent and p53-independent apoptosis

Mol Biol Cell. 2010 Jul 15;21(14):2453-68. doi: 10.1091/mbc.e09-12-1031. Epub 2010 May 19.


Nuclear receptor coactivator 6 (NCOA6) is a multifunctional protein implicated in embryonic development, cell survival, and homeostasis. An 81-amino acid fragment, dnNCOA6, containing the N-terminal nuclear receptor box (LXXLL motif) of NCOA6, acts as a dominant-negative (dn) inhibitor of NCOA6. Here, we expressed dnNCOA6 in postmitotic transgenic mouse lens fiber cells. The transgenic lenses showed reduced growth; a wide spectrum of lens fiber cell differentiation defects, including reduced expression of gamma-crystallins; and cataract formation. Those lens fiber cells entered an alternate proapoptotic pathway, and the denucleation (karyolysis) process was stalled. Activation of caspase-3 at embryonic day (E)13.5 was followed by double-strand breaks (DSBs) formation monitored via a biomarker, gamma-H2AX. Intense terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) signals were found at E16.5. Thus, a window of approximately 72 h between these events suggested prolonged though incomplete apoptosis in the lens fiber cell compartment that preserved nuclei in its cells. Genetic experiments showed that the apoptotic-like processes in the transgenic lens were both p53-dependent and p53-independent. Lens-specific deletion of Ncoa6 also resulted in disrupted lens fiber cell differentiation. Our data demonstrate a cell-autonomous role of Ncoa6 in lens fiber cell differentiation and suggest novel insights into the process of lens fiber cell denucleation and apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Apoptosis*
  • Caspase 3 / metabolism
  • Cataract / complications
  • Cataract / pathology
  • Cell Differentiation*
  • Enzyme Activation
  • Gene Deletion
  • In Situ Nick-End Labeling
  • Lens, Crystalline / abnormalities
  • Lens, Crystalline / metabolism
  • Lens, Crystalline / pathology*
  • Lens, Crystalline / ultrastructure
  • Mice
  • Mice, Transgenic
  • Microphthalmos / complications
  • Microphthalmos / pathology
  • Models, Biological
  • Nuclear Receptor Coactivators / chemistry*
  • Nuclear Receptor Coactivators / metabolism*
  • Organ Specificity
  • Proto-Oncogene Proteins c-maf / metabolism
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / metabolism*
  • gamma-Crystallins / metabolism


  • Ncoa6 protein, mouse
  • Nuclear Receptor Coactivators
  • Proto-Oncogene Proteins c-maf
  • Tumor Suppressor Protein p53
  • gamma-Crystallins
  • Caspase 3