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 Bieberich, Sarah MacKinnon, Jeane Silva, Scott Noggle, Brian G. Condie

Research output: Contribution to journalArticle

93 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)469-479
Number of pages11
JournalJournal of Cell Biology
Volume162
Issue number3
DOIs
StatePublished - Aug 4 2003

Keywords

  • Embryonic stem cells
  • Nestin
  • Neuronal differentiation
  • Neuroprogenitor
  • Sphingolipid

ASJC Scopus subject areas

  • Cell Biology

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