Essential role of mouse telomerase in highly proliferative organs

In the citing paper

“Similarly, in the testes, we observed the previously reported testicular atrophy and associated apoptotic depletion of germ cells in late-generation mTerc -/ -mice (32), with comparable reduction in testes weights ( P = 0.4131) and depletion of germ cells in all three Ink4a / Arf genotypes (Fig. 1 E ).”

In the citing paper

“Telomerase knock-out (mTERC−/−) mice which carry a homozygous deletion of the RNA component of telomerase (Blasco et al., 1997) show a generation-dependent telomere shortening, which results in critically short telomeres and both senescence and apoptosis (Lee et al., 1998).”

In the citing paper

“In the absence of telomerase, continued cell division results in telomere shortening, loss of ‘capping’ function, and p53 activation12-15.”

In the citing paper

“Due to the very long telomeres of Mus musculus, critical reduction in telomere length and chromosomal instability is only seen following extensive passage of mTR−/− cells (Niida et al. 1998”

In the citing paper

“This induction of p53 coincides with the dramatic increase in apoptosis (as assessed by TUNEL) and decreased cellularity in the G6 mTR−/− testis (Lee et al. 1998”

In the citing paper

“Loss of telomere function in late-generation (G4 onward) mTR−/− mice has been shown to adversely affect the morphology and physiology of diverse cell types and organ systems (Lee et al. 1998; Rudolph et al. 1999”

In the citing paper

“In the G6 mTR−/− p53+/− intercrosses, we observed an unusually high rate of productive mating pairs (11 of 22 mating pairs) compared to G6 mTR−/− p53+/+ matings (Lee et al. 1998”

In the citing paper

“In mTR−/− mice, a decrease in testis size that correlated with germ cell depletion by histology was first evident in G5 mTR−/− animals and became more prevalent in G6 mTR−/− mice (Lee et al. 1998”

In the citing paper

“In agreement with these findings, studies of telomerase knockout mice revealed short dysfunctional telomeres that profoundly impaired progenitor cell function in actively renewing tissues leading to atrophy and reduced regenerative potential, whereas more quiescent low-turnover tissues such as muscle were unaffected (Allsopp et al., 2003; Lee et al., 1998; Rudolph et al., 1999).”

In the citing paper

“Of note, late-generation Terc-deficient mice show some signs of accelerated aging (Lee et al., 1998; Rudolph et al., 1999”

In the citing paper

“Surprisingly, each telomerase component was found to be dispensable for life and these telomerase-knockout mice were remarkably normal (60).”

In the citing paper

“In the G5-G6 TERCÀ/À tissues, there was clear cytogenetic evidence of progressive telomere erosion including 'signal-free' ends, chromosomal end-to-end fusions and anaphase bridging at mitosis (60)(61)(62).”

In the citing paper

“The consequent signalling cascades activate checkpoints that induce either cellular senescence or apoptosis, and in at least some contexts both processes occur simultaneously82,85,91,95.”

In the citing paper

“The telomerase-knockout mouse has provided an important model for understanding telomere-mediated disease mechanisms because there is a remarkable convergence with human disease phenotypes (an overview is shown in Table 2)36,82,84,85,97,99–111.”

In the citing paper

“Although it was initially clear that high-turnover tissues are particularly sensitive to telomere length85,101,112”

In the citing paper

“In addition to promoting cell cycle arrest, dysfunctional telomeres can also activate p53-dependent apoptosis, since mice bearing dysfunctional telomeres show increased apoptosis in proliferative cells31-33.”

In the citing paper

“By the sixth generation (G6), increased apoptosis and compromised function were observed in highly proliferative tissues including skin, hematopoietic and reproductive systems31, 42-44.”

In the citing paper

“and the mice were no longer able to reproduce (15).”

In the citing paper

“by the seventh generation, highly proliferative organ systems like the testis, bone marrow, and spleen appeared abnormal”

In the citing paper

“In particular, mice carrying a homozygous germline deletion of the telomerase RNA component gene (Terc−/−) exhibit critically short telomeres and a premature development of age-related pathologies from the second or third generation [8, 18–20, 51, 70, 72, 101, 103]”

In the citing paper

“telomerase-deficient mice with short telomeres show reduced function of various stem cell compartments including those in the bone marrow and skin 58, 60”

In the citing paper

“the generation and characterization of the telomerase knockout mouse model has been instrumental in demonstrating that short telomeres result in multiple organismal defects caused by defective tissue regeneration 57, 58, 59”

In the citing paper

“In stem cell and progenitor cell compartments3–5, TERT serves an important role in keeping telomeres sufficiently long and stable to prevent the adverse consequences of dysfunctional telomeres on cell viability and chromosomal stability6–8.”