Lessons from Mice

Mice have by far longer telomeres than humans, which complicates a direct comparison of telomere-dependent replicative capacities in cells from both species. Nevertheless, valuable insights are given from telomerase-deficient mice, in which both alleles of mTERC, the murine RNA component of telomerase, are deleted. The first four to five generations of such mTERC-/- mice have unobtrusive pheno-types until telomeres get critically short. Then in following generations, similar to DKC patients, cytogenetic aberrations, a comprised bone marrow, immune deficiency, tumor formation, and an overall reduced life span appear in these telomerase-null mice (Blasco et al. 1997, Hande et al. 1999, Herrera et al. 1999, Rudolph et al. 1999). Wild-type mice HSCs already have a finite replicative life span, based upon their limitation to four to seven serial transplantations into irradiated mice (Harrison and Astle 1982, Harrison et al. 1978, Siminovitch et al. 1964). As in human HSCs, there seems to be telomere shortening despite telomerase activity in murine HSCs, resulting in more than 40% loss of total telomeric DNA after four rounds of serial transplantation (Allsopp et al. 2001, Allsopp et al. 2003b). Similar to the human situation, it is not yet clear how telomere shortening in HSCs is influencing the more differentiated offspring. However, it has been shown that stimulated T cells isolated from HSC transplant recipients could rejuvenate their telomeres by activation of telomerase (Allsopp et al. 2002). HSCs from telomerase-deficient mice, including the mTERC-/- mice above and mTERT-/- mice (Liu et al. 2000), can only be serially transplanted for two rounds due to an even accelerated telomere loss compared to wild-type controls (Allsopp et al. 2003a). This indicates a role for telomerase in HSCs in at least limiting the rate of telomere shortening during cell divisions to allow extended proliferation, the prerequisite of (hematopoietic) stem cell function throughout life.

In contrast to wild-type, transgenic mice overexpressing mTERT exhibit fourfold elevated levels of telomerase activity and stable telomeres during serial transplantations (Allsopp et al. 2003b). However, the transplantation capacity could not be increased for mTERT overexpressing HSCs, which indicates telomere-independent barriers for the transplantation of mice HSC, possibly reflecting a form of premature senescence or possible dilution and loss of real stem cells during serial transplantation (Allsopp et al. 2003b, Wright and Shay 2002). In a similar trans-genic mice strain overexpressing mTERT, the proliferation rate of hematopoietic cells is not elevated, although these mice are also characterized by increased telom-erase activity and maintained telomere length in hematopoietic and many other tissues compared to nontransgenic control mice (Artandi et al. 2002). Interestingly, robust TERT expression is accompanied by an increased susceptibility of breast cancer in aging females of these mice, which possibly indicates a direct oncogenic role of the enzyme (Artandi et al. 2002). Most recently, it was shown, that p21 deletion improved stem cell function without rescuing telomere function in mTERC knockout mice (Choudhury et al. 2007) (see also Gutierrez and Ju, this volume).

Finally, it seems that short telomeres themselves and not telomerase per se are limiting tissue renewal capacity. This raises questions about the importance of tel-omerase dosage effects on telomere length and disease phenotypes as seen above for DKC (Hao et al. 2005).

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