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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.

Bieberich E, MacKinnon S, Silva J, Noggle S, Condie BG - J. Cell Biol. (2003)

Bottom Line: Morpholino oligonucleotide-mediated antisense knockdown of PAR-4 or inhibition of ceramide biosynthesis reduced stem cell apoptosis, whereas PAR-4 overexpression and treatment with ceramide analogs elevated apoptosis.In mitotic cells, asymmetric distribution of PAR-4 and nestin resulted in one nestin(-)/PAR-4(+) daughter cell, in which ceramide elevation induced apoptosis.Asymmetric distribution of PAR-4 and simultaneous elevation of endogenous ceramide provides a possible mechanism underlying asymmetric differentiation and apoptosis of neuronal stem cells in the developing brain.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, Room CB-2803, Augusta, GA 30912, USA. ebieberich@mail.mcg.edu

ABSTRACT
Cell death and survival of neural progenitor (NP) cells are determined by signals that are largely unknown. We have analyzed pro-apoptotic signaling in individual NP cells that have been derived from mouse embryonic stem cells. NP formation was concomitant with elevated apoptosis and increased expression of ceramide and prostate apoptosis response 4 (PAR-4). Morpholino oligonucleotide-mediated antisense knockdown of PAR-4 or inhibition of ceramide biosynthesis reduced stem cell apoptosis, whereas PAR-4 overexpression and treatment with ceramide analogs elevated apoptosis. Apoptotic cells also stained for proliferating cell nuclear antigen (a nuclear mitosis marker protein), but not for nestin (a marker for NP cells). In mitotic cells, asymmetric distribution of PAR-4 and nestin resulted in one nestin(-)/PAR-4(+) daughter cell, in which ceramide elevation induced apoptosis. The other cell was nestin(+), but PAR-4(-), and was not apoptotic. Asymmetric distribution of PAR-4 and simultaneous elevation of endogenous ceramide provides a possible mechanism underlying asymmetric differentiation and apoptosis of neuronal stem cells in the developing brain.

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A model for asymmetric apoptosis of NP daughter cells due to the asymmetric distribution of nestin and PAR-4 proteins. Before mitosis or during S-phase, NP cells up-regulate the expression of nestin, PAR-4, and ceramide. During cell division, ceramide is distributed equally to the daughter cells, whereas PAR-4 and nestin are restricted to different daughter cells. The daughter cell with simultaneous presence of PAR-4 and ceramide will die due to apoptosis, whereas the one containing ceramide and nestin will again divide or differentiate. Conversion of ceramide to sphingomyelin and/or glycosphingolipids due to up-regulation of sphingomyelin or glucosyl- or galactosylceramide biosynthesis protects this cell from apoptosis on further cell division or differentiation.
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fig10: A model for asymmetric apoptosis of NP daughter cells due to the asymmetric distribution of nestin and PAR-4 proteins. Before mitosis or during S-phase, NP cells up-regulate the expression of nestin, PAR-4, and ceramide. During cell division, ceramide is distributed equally to the daughter cells, whereas PAR-4 and nestin are restricted to different daughter cells. The daughter cell with simultaneous presence of PAR-4 and ceramide will die due to apoptosis, whereas the one containing ceramide and nestin will again divide or differentiate. Conversion of ceramide to sphingomyelin and/or glycosphingolipids due to up-regulation of sphingomyelin or glucosyl- or galactosylceramide biosynthesis protects this cell from apoptosis on further cell division or differentiation.

Mentions: Based on these observations, we suggest a model for asymmetric cell division, apoptosis, and differentiation of neuronal stem cells, shown in Fig. 10. Differentiating stem cells up-regulate the expression of nestin, ceramide, and PAR-4 before or during cell division. Ceramide and PAR-4 elevation at these stages is most likely caused by up-regulation of gene expression for PAR-4 and SPT subunit 1 (SPT1) in EB8. This indicates regulation of de novo ceramide biosynthesis and PKCζ activity by the respective regulatory proteins, but not by basal enzyme activities. During mitosis, ceramide is evenly sequestered to the two daughter cells, whereas PAR-4 and nestin are asymmetrically distributed. The nestin(−)/PAR-4(+) daughter cell undergoes ceramide-induced apoptosis, whereas the nestin(+)/PAR-4(−) daughter cell may again divide or further differentiate into a neuronal or glial precursor cell. At this point, rapid passage of the mitotic cycle is desirable in order to sequester PAR-4 to one daughter cell and to avoid abortive mitosis before accomplishment of cell division (Liu and Greene, 2001).


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.

Bieberich E, MacKinnon S, Silva J, Noggle S, Condie BG - J. Cell Biol. (2003)

A model for asymmetric apoptosis of NP daughter cells due to the asymmetric distribution of nestin and PAR-4 proteins. Before mitosis or during S-phase, NP cells up-regulate the expression of nestin, PAR-4, and ceramide. During cell division, ceramide is distributed equally to the daughter cells, whereas PAR-4 and nestin are restricted to different daughter cells. The daughter cell with simultaneous presence of PAR-4 and ceramide will die due to apoptosis, whereas the one containing ceramide and nestin will again divide or differentiate. Conversion of ceramide to sphingomyelin and/or glycosphingolipids due to up-regulation of sphingomyelin or glucosyl- or galactosylceramide biosynthesis protects this cell from apoptosis on further cell division or differentiation.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2172704&req=5

fig10: A model for asymmetric apoptosis of NP daughter cells due to the asymmetric distribution of nestin and PAR-4 proteins. Before mitosis or during S-phase, NP cells up-regulate the expression of nestin, PAR-4, and ceramide. During cell division, ceramide is distributed equally to the daughter cells, whereas PAR-4 and nestin are restricted to different daughter cells. The daughter cell with simultaneous presence of PAR-4 and ceramide will die due to apoptosis, whereas the one containing ceramide and nestin will again divide or differentiate. Conversion of ceramide to sphingomyelin and/or glycosphingolipids due to up-regulation of sphingomyelin or glucosyl- or galactosylceramide biosynthesis protects this cell from apoptosis on further cell division or differentiation.
Mentions: Based on these observations, we suggest a model for asymmetric cell division, apoptosis, and differentiation of neuronal stem cells, shown in Fig. 10. Differentiating stem cells up-regulate the expression of nestin, ceramide, and PAR-4 before or during cell division. Ceramide and PAR-4 elevation at these stages is most likely caused by up-regulation of gene expression for PAR-4 and SPT subunit 1 (SPT1) in EB8. This indicates regulation of de novo ceramide biosynthesis and PKCζ activity by the respective regulatory proteins, but not by basal enzyme activities. During mitosis, ceramide is evenly sequestered to the two daughter cells, whereas PAR-4 and nestin are asymmetrically distributed. The nestin(−)/PAR-4(+) daughter cell undergoes ceramide-induced apoptosis, whereas the nestin(+)/PAR-4(−) daughter cell may again divide or further differentiate into a neuronal or glial precursor cell. At this point, rapid passage of the mitotic cycle is desirable in order to sequester PAR-4 to one daughter cell and to avoid abortive mitosis before accomplishment of cell division (Liu and Greene, 2001).

Bottom Line: Morpholino oligonucleotide-mediated antisense knockdown of PAR-4 or inhibition of ceramide biosynthesis reduced stem cell apoptosis, whereas PAR-4 overexpression and treatment with ceramide analogs elevated apoptosis.In mitotic cells, asymmetric distribution of PAR-4 and nestin resulted in one nestin(-)/PAR-4(+) daughter cell, in which ceramide elevation induced apoptosis.Asymmetric distribution of PAR-4 and simultaneous elevation of endogenous ceramide provides a possible mechanism underlying asymmetric differentiation and apoptosis of neuronal stem cells in the developing brain.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th Street, Room CB-2803, Augusta, GA 30912, USA. ebieberich@mail.mcg.edu

ABSTRACT
Cell death and survival of neural progenitor (NP) cells are determined by signals that are largely unknown. We have analyzed pro-apoptotic signaling in individual NP cells that have been derived from mouse embryonic stem cells. NP formation was concomitant with elevated apoptosis and increased expression of ceramide and prostate apoptosis response 4 (PAR-4). Morpholino oligonucleotide-mediated antisense knockdown of PAR-4 or inhibition of ceramide biosynthesis reduced stem cell apoptosis, whereas PAR-4 overexpression and treatment with ceramide analogs elevated apoptosis. Apoptotic cells also stained for proliferating cell nuclear antigen (a nuclear mitosis marker protein), but not for nestin (a marker for NP cells). In mitotic cells, asymmetric distribution of PAR-4 and nestin resulted in one nestin(-)/PAR-4(+) daughter cell, in which ceramide elevation induced apoptosis. The other cell was nestin(+), but PAR-4(-), and was not apoptotic. Asymmetric distribution of PAR-4 and simultaneous elevation of endogenous ceramide provides a possible mechanism underlying asymmetric differentiation and apoptosis of neuronal stem cells in the developing brain.

Show MeSH