Loss of nicastrin elicits an apoptotic phenotype in mouse embryos.
Nicastrin is a member of the high molecular weight presenilin complex that plays a central role in gamma-secretase cleavage of numerous type-1 membrane-associated proteins required for cell signaling, proliferation and lineage development. We have generated a nicastrin-null mouse line by disruption of exon 3. Similar to previously described nicastrin-null mice, these animals demonstrate severe growth retardation, mortality beginning at embryonic age 10.5 days, and marked developmental abnormalities indicative of a severe Notch phenotype. Preceding their mortality, 10.5-day-old nicastrin-null embryos were found to also exhibit specific apoptosis within regions showing profound deformities, particularly in the developing heart and brain. This result suggests that complete disruption of presenilin complexes elicits programmed cell death, in addition to a Notch phenotype, which may contribute to the developmental abnormalities and embryonic mortality of nicastrin-null mice and possibly neurodegeneration in Alzheimer's disease.
Nguyen
Van
V
Dept. of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
Hawkins
Cynthia
C
Bergeron
Catherine
C
Supala
Agnes
A
Huang
Jean
J
Westaway
David
D
St George-Hyslop
Peter
P
Rozmahel
Richard
R
D000367:Age Factors; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004622:Embryo, Mammalian / Q000502:physiology*; D005260:Female; D018390:Gene Targeting; D005838:Genotype; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011247:Pregnancy
D008562:Membrane Glycoproteins; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases