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First published online April 22, 2004
doi: 10.1242/10.1242/dev.01082

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Apaf1-dependent programmed cell death is required for inner ear morphogenesis and growth

¹ Dulbecco Telethon Institute, Department of Biology, University of Rome `Tor Vergata', via della Ricerca Scientifica, 00133 Rome, Italy
² Department of Pathology, University of Alabama at Birmingham, SC 961E, 1530 Third Avenue South, Birmingham, AL 35294, USA
³ P. K. Anokhin Institute of Normal Physiology RAMS, 6, Bol. Nikitskaya st, 103009 Moscow, Russia
⁴ Department of Molecular Cell Biology, Max-Planck Institute of Biophysical Chemistry, Am Fassberg 11, 37077 Goettingen, Germany
⁵ Institute of Biotechnology, University of Helsinki, Viikinkaari 9, 00710 Helsinki, Finland

^* Author for correspondence (e-mail: marjo.salminen{at}helsinki.fi)

Accepted 19 January 2004

During inner ear development programmed cell death occurs in specific areas of the otic epithelium but the significance of it and the molecules involved have remained unclear. We undertook an analysis of mouse mutants in which genes encoding apoptosis-associated molecules have been inactivated. Disruption of the Apaf1 gene led to a dramatic decrease in apoptosis in the inner ear epithelium, severe morphogenetic defects and a significant size reduction of the membranous labyrinth, demonstrating that an Apaf1-dependent apoptotic pathway is necessary for normal inner ear development. This pathway most probably operates through the apoptosome complex because caspase 9 mutant mice suffered similar defects. Inactivation of the Bcl2-like (Bcl2l) gene led to an overall increase in the number of cells undergoing apoptosis but did not cause any major morphogenetic defects. In contrast, decreased apoptosis was observed in specific locations that suffered from developmental deficits, indicating that proapoptotic isoform(s) produced from Bcl2l might have roles in inner ear development. In Apaf1^-/-/Bcl2l^-/- double mutant embryos, no cell death could be detected in the otic epithelium, demonstrating that the cell death regulated by the anti-apoptotic Bcl2l isoform, Bcl-X_L in the otic epithelium is Apaf1-dependent. Furthermore, the otic vesicle failed to close completely in all double mutant embryos analyzed. These results indicate important roles for both Apaf1 and Bcl2l in inner ear development.

Key words: Apoptosis, Bcl2l, Bcl-X_L, Bcl-X_S, Caspase 9, Proliferation, Otic vesicle closure, Semicircular ducts, Cochlea, Mouse

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