Disease states associated with telomerase deficiency appear earlier in mice with short telomeres.
Mice deficient for the mouse telomerase RNA (mTR-/-) and lacking telomerase activity can only be bred for approximately six generations due to decreased male and female fertility and to an increased embryonic lethality associated with a neural tube closure defect. Although late generation mTR-/- mice show defects in the hematopoietic system, they are viable to adulthood, only showing a decrease in viability in old age. To assess the contribution of genetic background to the effect of telomerase deficiency on viability, we generated mTR-/- mutants on a C57BL6 background, which showed shorter telomeres than the original mixed genetic background C57BL6/129Sv. Interestingly, these mice could be bred for only four generations and the survival of late generation mTR-/- mice decreased dramatically with age as compared with their wild-type counterparts. Fifty percent of the generation 4 mice die at only 5 months of age. This decreased viability with age in the late generation mice is coincident with telomere shortening, sterility, splenic atrophy, reduced proliferative capacity of B and T cells, abnormal hematology and atrophy of the small intestine. These results indicate that telomere shortening in mTR-/- mice leads to progressive loss of organismal viability.
Herrera
E
E
Department of Immunology and Oncology, Centro Nacional de Biotecnología-CSIC, Campus Cantoblanco, E-28049 Madrid, Spain.
Samper
E
E
Martín-Caballero
J
J
Flores
J M
JM
Lee
H W
HW
Blasco
M A
MA
D000375:Aging / Q000235:genetics; D000818:Animals; D001284:Atrophy; D001835:Body Weight; D002478:Cells, Cultured; D003433:Crosses, Genetic; D005260:Female; D005804:Genes, Lethal / Q000235:genetics; D006413:Hematopoietic System / Q000473:pathology; D007246:Infertility / Q000235:genetics*; D007421:Intestine, Small / Q000473:pathology; D007958:Leukocyte Count; D008136:Longevity / Q000235:genetics*; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000473:pathology / Q000503:physiopathology; D019098:Telomerase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000502:physiology*; D013737:Testis / Q000473:pathology; D013997:Time Factors
D019098:Telomerase