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J. Biol. Chem., Vol. 281, Issue 39, 28782-28793, September 29, 2006

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Yaf2 Inhibits Caspase 8-mediated Apoptosis and Regulates Cell Survival during Zebrafish Embryogenesis^*

Sasha E. Stanton, Lisa J. McReynolds, Todd Evans, and Nicole Schreiber-Agus¹

From the Departments of Molecular Genetics and Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461

Rybp (DEDAF) is a member of the Rybp/Yaf2 protein family and has been shown to encode pro-apoptotic functions and to be essential for mouse embryogenesis. The related Yaf2 protein has not been studied extensively at the cellular or organismal levels. Here we describe zebrafish yaf2 (zyaf2) and show that it is widely expressed during early embryogenesis, with subsequent enrichment of transcripts in the anterior head region. Depletion of zYaf2 during embryogenesis using specific morpholinos activates a wide-spread program of apoptosis and causes developmental arrest before the one somite stage. Partial depletion of Yaf2, achieved by injecting lower dosages of morpholino, circumvents the early arrest but leads to CNS degeneration associated with excessive apoptosis. These phenotypes can be rescued by co-injection of human YAF2 mRNA with the morpholinos or by treatment with a pan-caspase inhibitor or a caspase 8-specific inhibitor. Finally, the observed activation of caspase 8 in the morphants is in accord with the ability of Yaf2 to inhibit caspase 8-mediated apoptosis in cultured cells. Our findings implicate Yaf2 as a survival factor during early zebrafish development and organogenesis. This may suggest that Yaf2 and Rybp can encode opposing functions in the regulation of apoptosis.

Received for publication, April 7, 2006 , and in revised form, August 3, 2006.

^* This work was supported in part by National Institutes of Health Public Health Service Grants CA92558 (to N. S.-A.) and HL64282 and HL56182 (to T. E.), and National Institutes of Health Medical Scientist Training Program Grant T32 GM07288 (to S. E. S. and L. J. M.). This work was also supported by the Irma T. Hirschl Trust (to T. E.) and the Albert Einstein Cancer Center (to N. S.-A. and T. E.). 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.

Data in this paper are from a thesis (S. E. S.) to be submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate Division of Medical Sciences, Albert Einstein College of Medicine, Yeshiva University.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Dept. of Molecular Genetics, 1300 Morris Park Ave., Ullmann 809, Bronx, NY 10461. Tel.: 718-430-3216; Fax: 718-430-8778; E-mail: agus{at}aecom.yu.edu.

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