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. 2004 Apr 20;101(16):6080-5.
doi: 10.1073/pnas.0401580101. Epub 2004 Apr 12.

Distinct dosage requirements for the maintenance of long and short telomeres in mTert heterozygous mice

Natalie Erdmann  1 , Yie Liu, Lea Harrington
Affiliations

Distinct dosage requirements for the maintenance of long and short telomeres in mTert heterozygous mice

Natalie Erdmann et al. Proc Natl Acad Sci U S A. .

Abstract

Telomerase is a ribonucleoprotein containing an essential telomerase RNA template and telomerase reverse transcriptase (TERT) that maintains telomeres. The dosage requirements for mammalian TERT in telomere length homeostasis are not known, but are of importance in cellular senescence, stem cell renewal, and cancer. Here, we characterize telomere maintenance and function upon successive breeding of mice deficient in mTert. These studies reveal a unique dosage requirement for telomere length maintenance by TERT; despite haploinsufficiency for the maintenance of long telomeres, mTert+/- mice retain minimal telomere DNA at all chromosome ends and do not exhibit the infertility typical of telomerase-deficient strains. Unlike the long (>50 kbp) average telomere lengths of wild-type laboratory mice, mTert+/- animals mice possess short telomere lengths similar to humans and wild-derived mice. Unexpectedly, mTert+/- mice are ersatz carriers for genetic instability, because their mating led to accelerated genetic instability and infertility in null progeny. Thus, limiting TERT levels play a key role in the maintenance of genome integrity, with important ramifications for the maintenance of short telomeres in human cancer and aging.

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Figures

Fig. 1.
Fig. 1.
Mating scheme and litter sizes. (Upper) Schematic diagram of breeding strategy used to generate mTert-/- mice in a mixed (C57BL/6/129) or C57BL/6 genetic background. See Materials and Methods for details. (Lower) Total number of pups, divided by the number of mating pairs, produced in 6 months in mixed (light gray) and C57BL/6 (dark gray) mTert-/- mice. In the mixed background, the number of mating pairs analyzed were n = 2 (G1, G2, and G5), n = 3 (G3 and G4), n = 4 (G6), n = 6 (G7), and n = 9 (G8). In C57BL/6, the number of mating pairs analyzed were n = 10 (G1), n = 6 (G2), n = 11 (G3), and n = 7 (G4).
Fig. 2.
Fig. 2.
Telomere length analysis of mTert-/- mice in two different genetic backgrounds. (A) Q-FISH analysis from wild-type (wt), G6, G7, and G8 mTert-/- mice in a mixed C57BL/6/129 genetic background (Mixed). Each histogram represents 400 chromosomes from one mouse (at least two mice were analyzed from each generation, one representative mouse is shown). The arrows indicate the mean telomere length of the mouse represented. See Table 1 for quantification of cytogenetic data. (B) Q-FISH analysis from wild-type, G2, G3, and G4 mTert-/- mice in a C57BL/6 genetic background (Bl/6). Each histogram represents 400 chromosomes from one mouse (at least two mice were analyzed from each generation, one representative mouse is shown). The arrows indicate the mean telomere length of the mouse represented. See Table 1 for quantification of cytogenetic data. The x axes indicate telomere fluorescence signal intensity (in arbitrary units) for each chromosome end, with each tick mark representing 50 arbitrary units, and y axes indicate the number of ends (events) in each signal intensity category. Telomere SFEs are the events shown at “zero” arbitrary telomere fluorescence units on the x axis.
Fig. 3.
Fig. 3.
Telomere length analysis in backcrossed mTert+/- mice. (Top and Middle) Q-FISH analysis from 7th, 8th, 9th, and 10th generation mTert+/+ and mTert+/- littermates (black) from mTert+/- mice successively backcrossed to wild-type C57BL/6 mice (The Jackson Laboratory). In each case, a C57BL/6 mouse analyzed concurrently with each littermate pair is overlaid for comparison (gray). (Bottom) Q-FISH analysis from wildtype (gray) and G3 and G4 mTert-/- mice (black), reproduced from Fig. 2 for comparison. Note the absence of SFE in mTert+/- mice. For unknown reasons, all BC8+/- mice showed a slightly shorter average telomere length than BC9+/- and BC10+/- mice. Axes are labeled as in Fig. 2. The arrows indicate the mean telomere length of each mouse analyzed (solid arrows indicate mTert+/+, mTert+/- or mTert-/- mice; open arrows indicate wild-type C57BL/6 control mice).
Fig. 4.
Fig. 4.
Telomere length and cytogenetic analysis of mTert-/- and mTert+/- mice obtained from intergeneration crosses. (Top) Mating scheme for obtaining iF1 mTert-/- and mTert+/- mice (see text for details). (Middle) Q-FISH analysis of BC8 mTert+/- and G7 mTert-/- mice (the actual distributions shown are from littermates of the parents) and iF1 mTert-/- and iF1 mTert+/- littermates. Axes are labeled as in Fig. 2. (Bottom) Cytogenetic analysis of the mice shown above. See Table 1 for detailed explanation of each measurement. a, Expressed in milligrams. Data for B6 WT, BC8+/-, and G7-/- are reproduced from Table 1. The testes measured in iF1 animals (-/-, 3; +/-, 5) were taken from older, larger animals and are proportionate to total body mass.
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