Characterization Of Mice Without Telomerase

To address directly the potential role of telomerase in cancer and aging, four different telomerase-deficient mouse models have been generated to date. In two of the models, the gene encoding the telomerase RNA component Terc was eliminated from the mouse germ line (14,42); these mice lack telomerase activity, although they still express the Tert subunit (23). In two different knockout models, the gene coding for Tert was eliminated (43,44). The phenotypes of the four telomerase knockout mice appear to be identical, suggesting that the catalytic subunit and the telomerase RNA are essential for telomerase activity, and that they do not seem to have differential roles in the cell. This chapter will focus mainly on the extensively studied mouse telomerase knockout model, Terc~'~ mice, originally described by Blasco and coworkers. (14).

A. Telomeric Shortening in the Absence of Telomerase

Since mouse telomeres are very long (~40 kb of average length in some mouse strains), it has been possible to derive several Terc~'~ mouse generations before loss of viability is observed in the colony. As expected from the absence of telomerase activity, Terc~'~ mice show progressive telomeric shortening with increasing mouse generations in different adult cell types. Figure 2 shows telomeric quantitative fluorescence in situ hybridization (FISH) on metaphases from early (p1) and late passage (p50) wild-type and G6 Terc~'~ mouse embryonic

t WT IUI EP p1

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