Yang X, Klein R, Tian X, Cheng HT, Kopan R, Shen J.
Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway.
Dev Biol. 2004 May 1;269(1):81-94.
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In this study, the authors investigate the role of notch signaling during mammalian neural development. The authors use a number of intricate, crafty conditional knockout mouse models to address whether notch signaling regulates apoptotic cell death during mammalian neural development. The data are very strong, and the figures very crisp. By selectively expressing the notch intracellular domain (NICD) in progenitor cells the authors demonstrated extensive apoptotic cell death via a p53-dependent pathway. This effect was not observed in postmitotic neurons, indicating a developmental sensitivity of neurons to notch signaling.
To firm up these observations, the authors used an alternative strategy of attenuating notch activity again by using a conditional knockout strategy or by using PS-1 null mice. In this experimental paradigm, the authors show an opposite effect whereby in both conditions, there was a reduction in cell death of neural progenitor cells. These results provide further insight into the role of notch signaling during neuronal development. In addition, these results are interesting when compared to either the Saura et al. or Feng et al. study in adult PS-1 or PS-2 brain knockouts, which both demonstrate massive neuronal degeneration. Clearly, there are proteins that are probably regulated in a developmental fashion that can lead to a differential sensitivity of neurons to notch signaling in progenitor versus postmitotic cells. Further studies should shed light on additional players in this important signaling pathway.
Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, Chattarji S, Kelleher RJ 3rd, Kandel ER, Duff K, Kirkwood A, Shen J.
Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration.
Neuron. 2004 Apr 8;42(1):23-36.
Feng R, Wang H, Wang J, Shrom D, Zeng X, Tsien JZ.
Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2.
Proc Natl Acad Sci U S A. 2004 May 25;101(21):8162-7.