Apoptotic cells (green) are PAR-4 positive (red).

Programmed cell death is essential for preventing hyperproliferation during normal embryonic brain development and is also critical to the pathogenesis of several neurodegenerative diseases. Using mouse embryonic stem cells to model neuronal differentiation, Bieberich et al. (page 469) now show that when neural progenitor cells divide, only one progeny cell survives due to asymmetric distribution of pro- and anti-apoptotic factors between daughter cells.

In the developing mouse brain, apoptosis often correlates with the presence of the lipid ceramide and the protein PAR-4, and current models predict that neuronal apoptosis follows soon after cell division. The authors found that, in neuronal progenitors derived from embryonic stem cells, PAR-4 and the intermediate filament protein nestin (a marker of neural progenitors) are asymmetrically distributed after mitosis. One daugher cell inherits high PAR-4 and low nestin levels, and undergoes apoptosis. The other daughter inherits low PAR-4 and high nestin levels, and survives. Ceramide apparently induces apoptosis in the PAR-4–positive cell but not in the nestin-positive cell, possibly through active destruction of ceramide in the surviving daughter. The authors are now trying to determine how ceramide and PAR-4 interact to induce cell death and also hope to identify the mechanism that ensures asymmetric inheritance of PAR-4 and nestin. ▪