Regulation of cell death in mitotic neural progenitor cells by asymmetric distribution of prostate apoptosis response 4 (PAR-4) and simultaneous elevation of endogenous ceramide

doi:10.1083/jcb.200212067

Published online 28 July 2003. doi:10.1083/jcb.200212067

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© The Rockefeller University Press, 0021-9525/2003/8/469 $5.00
The Journal of Cell Biology, Volume 162, Number 3, 469-479

Article

Regulation of cell death in mitotic neural progenitor cells by asymmetric distribution of prostate apoptosis response 4 (PAR-4) and simultaneous elevation of endogenous ceramide

Erhard Bieberich¹^,2, Sarah MacKinnon¹, Jeane Silva¹, Scott Noggle¹^,3 and Brian G. Condie¹^,2^,3

¹ Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912
² Department of Medicine, Medical College of Georgia, Augusta, GA 30912
³ Department of Genetics, University of Georgia, Athens, GA 30602

Address correspondence to Erhard Bieberich, Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, Room CB-2803, Augusta, GA 30912. Tel.: (706) 721-9113. Fax: (706) 721-8685. email: ebieberich{at}mail.mcg.edu

Cell death and survival of neural progenitor (NP) cells aredetermined by signals that are largely unknown. We have analyzedpro-apoptotic signaling in individual NP cells that have beenderived from mouse embryonic stem cells. NP formation was concomitantwith elevated apoptosis and increased expression of ceramideand prostate apoptosis response 4 (PAR-4). Morpholino oligonucleotide-mediatedantisense knockdown of PAR-4 or inhibition of ceramide biosynthesisreduced stem cell apoptosis, whereas PAR-4 overexpression andtreatment with ceramide analogs elevated apoptosis. Apoptoticcells also stained for proliferating cell nuclear antigen (anuclear mitosis marker protein), but not for nestin (a markerfor NP cells). In mitotic cells, asymmetric distribution ofPAR-4 and nestin resulted in one nestin(-)/PAR-4(+) daughtercell, in which ceramide elevation induced apoptosis. The othercell was nestin(+), but PAR-4(-), and was not apoptotic. Asymmetricdistribution of PAR-4 and simultaneous elevation of endogenousceramide provides a possible mechanism underlying asymmetricdifferentiation and apoptosis of neuronal stem cells in thedeveloping brain.

Key Words: embryonic stem cells; neuronal differentiation; neuroprogenitor; sphingolipid; nestin

Abbreviations used in this paper: Bcl-2, b-cell lymphoma 2;EB, embryoid body; ES, embryonic stem; FB1, fumonisin B1; FGF-2,fibroblast growth factor 2; HPTLC, high performance thin layerchromatography; NP, neural progenitor; PAR-4, prostate apoptosisresponse 4; PCNA, proliferating cell nuclear antigen; SPT, serinepalmitoyltransferase.

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