September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Lens differentiation rides the wave of p27Kip1 to lens fiber cell denucleation
Author Affiliations & Notes
  • Allen Taylor
    Tufts University, Boston, Massachusetts, United States
  • Sheldon Rowan
    Tufts University, Boston, Massachusetts, United States
  • Min-Lee Chang
    Tufts University, Boston, Massachusetts, United States
  • Fu Shang
    Tufts University, Boston, Massachusetts, United States
  • Natalie Reznikov
    Department of Materials, Imperial College, London, United Kingdom
  • Lei Lyu
    Tufts University, Boston, Massachusetts, United States
    Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, Sichuan, China
  • Ke Liu
    Tufts University, Boston, Massachusetts, United States
    Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, Sichuan, China
  • Footnotes
    Commercial Relationships   Allen Taylor, None; Sheldon Rowan, None; Min-Lee Chang, None; Fu Shang, None; Natalie Reznikov, None; Lei Lyu, None; Ke Liu, None
  • Footnotes
    Support  NIH (RO1EY012121, RO1EY13250) and USDA (under agreement #58-1950-0-014 and #58-1950-4-003) to A.T.
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Allen Taylor, Sheldon Rowan, Min-Lee Chang, Fu Shang, Natalie Reznikov, Lei Lyu, Ke Liu; Lens differentiation rides the wave of p27Kip1 to lens fiber cell denucleation. Invest. Ophthalmol. Vis. Sci. 201657(12):.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : The eye lens is unique among tissues. Using the same building blocks as are used to create the opaque tissues, the lens is clear. It does not form tumors, and the majority of its cells destroy their organelles, including their nuclei. A mystery for over a century, there has been considerable recent progress in elucidating mechanisms of lens fiber cell denucleation (LFCD). The cumulative evidence indicates that the unidirectional process of LFCD utilizes cellular machinery from the cyclic events of mitosis to initiate nuclear envelope breakdown.

Methods : Using cell free and in vitro cell culture systems, as well as laboratory animals, along with biochemical, and histologic techniques, including Focused Ion Beam Electron Microscopy, we monitored the cyclin-dependent kinase inhibitor, p27Kip1, cyclin-dependent kinase 1 (Cdk1), nuclear lamins, DNaseIIβ (DLAD), ubiquitin proteasome system (UPS) and the unfolded protein response (UPR), Calcium, calpain activity, and cell nucleus disassembly.

Results : Multiple cellular pathways, including the UPS and the UPR, converge on post-translational regulation of p27Kip1. p27Kip1 is degraded, liberating a wave of Cdk1 activity. This results in phosphorylation of nuclear lamins, dissociation of the nuclear membrane, and entry of lysosomes that liberate DLAD to cleave chromatin. Failed UPS results in stabilization of p27Kip1; inhibition of Cdk1 activity; stabilization of Connexin 46; elevation of Ca2+, elevation of calpain activity, unscheduled, cataract-related cleavage of multiple major lens proteins; and a delayed differentiation program associated with lack of LFCD. Mouse models with an activated UPR in the lens also exhibited stabilized p27Kip1, inhibition of Cdk1 activity, failed LFCD, and congenital cataract.

Conclusions : Mutations that impair these pathways cause congenital cataracts, associated with loss of LFCD. These findings highlight new regulatory nodes in the lens and suggest that we are close to understanding this fascinating final step in the most terminal differentiation process of the body. Such knowledge may offer a new means to confront proliferative diseases including cancer.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×