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J. Biol. Chem., Vol. 280, Issue 34, 30263-30272, August 26, 2005

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Role of the Executioner Caspases during Lens Development^*

Anna J. Zandy, Saquib Lakhani¶, Timothy Zheng||, Richard A. Flavell¶**, and Steven Bassnett

From the Department of Ophthalmology and Visual Sciences and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, the ^¶Section of Immunobiology and ^**Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520, and ^||Biogen Idec Inc., Cambridge, Massachusetts 02142

The notion that the cell death machinery is utilized during lens organelle degradation is supported by the observation that well characterized apoptotic substrates are cleaved during this process. Here, we test directly the role of executioner caspases (caspase-3, -6, and -7) in fiber cell differentiation. The distribution of mRNA, protein, and enzymatic activity for each caspase was determined in the mouse lens. Transcripts for all three executioner caspases were identified in lens fiber cells by real time RT-PCR, although only caspase-6 and -7 proteins were detected subsequently by Western blot analysis. Endogenous proteolytic activity was noted for caspase-3 but not caspase-6 or -7. We tested the role of executioner caspases in organelle degradation by examining lenses from mice deficient in each caspase. Knock-out lenses appeared grossly normal with the exception of caspase-3^-/- lenses, which exhibited marked cataracts at the anterior lens pole. The distribution of lens organelles was mapped by confocal microscopy. There was no significant difference in the size of the lens organelle-free zone (OFZ)¹ between wild-type and knock-out lenses. In response to treatment with staurosporine, caspase-3 and -6 (but not caspase-7) enzymatic activities were induced. We generated double knock-out animals to examine the phenotype of lenses deficient in both caspase-3 and -6. Histological examination of such lenses indicated the presence of a properly formed OFZ. Thus, no single executioner caspase (nor a combination of caspase-3 and -6) is required for organelle loss, although caspase-3 activity may be required for other aspects of lens transparency.

Received for publication, April 13, 2005 , and in revised form, June 29, 2005.

^* This study was supported by National Institutes of Health Grants R01EY009852 and R01EY012260 (to S. B.) and EY02687 (core grant for vision research) and an unrestricted grant to the Department of Ophthalmology and Sciences from Research to Prevent Blindness (to R. P. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

An Investigator of the Howard Hughes Medical Institute.

A William and Mary Greve RPB scholar.

To whom correspondence should be addressed: Dept. of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8096, St. Louis, MO 63110. Tel.: 314-362-1650; Fax: 314-362-3638; E-mail: ajzandy{at}artsci.wustl.edu.

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