Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline

Graniel, J. V.; Bisht, K.; Friedman, A.; White, J.; Perkey, E.; Vanderbeck, A.; Moroz, A.; Carrington, L. J.; Brandstadter, J. D.; Allen, F.; Shami, A. N.; Thomas, P.; Crayton, A.; Manzor, M.; Mychalowych, A.; Chase, J.; Hammoud, S. S.; Keegan, C. E.; Maillard, I.; Nandakumar, J.

doi:10.1101/2021.07.29.454392

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bioRxiv · 10.1101/2021.07.29.454392

Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline

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Abstract

Telomerase extends chromosome ends in somatic and germline stem cells to ensure continued proliferation. Mutations in genes critical for telomerase function result in telomeropathies such as dyskeratosis congenita (DC), frequently resulting in spontaneous bone marrow failure. While knockout of telomerase in mice has been instrumental in highlighting the importance of telomere length maintenance at an organismal level, it may not be representative of human telomeropathy mutations in vivo. A DC mutation in the shelterin protein TPP1 (K170{Delta}) that compromises telomerase recruitment to telomeres but leaves other functions of TPP1 and the integrity of the telomerase holoenzyme intact is a physiologically relevant tool to evaluate telomerase-dependent telomere length maintenance in mice. We used CRISPR-Cas9 to generate a mutant mouse knocked in for the equivalent of the TPP1 K170{Delta} mutation (TPP1 K82{Delta}) and investigated both its bone marrow and germline compartments in unprecedented detail. TPP1 K82{Delta} caused progressive telomere erosion with increasing generation number but did not induce steady-state hematopoietic defects. Strikingly, K82{Delta} caused mouse infertility, consistent with gross morphological defects in the testis and sperm, the appearance of either empty or severely disorganized seminiferous tubules, and a decrease in both spermatogonia and spermatocytes. It is intriguing that both TPP1 K82{Delta} mice and previously characterized telomerase knockout mice show no spontaneous bone marrow failure but rather succumb to a robust infertility phenotype at steady state. We speculate that telomere length maintenance contributes differently to the evolutionary fitness of humans and mice. Telomere length maintenance in the human bone marrow can ensure progression to reproductive age, while that in the mouse germline can help meet the elevated demand for sperm to produce multiple offspring.

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Graniel, J. V., Bisht, K., Friedman, A., White, J., Perkey, E., Vanderbeck, A., Moroz, A., Carrington, L. J., Brandstadter, J. D., Allen, F., Shami, A. N., Thomas, P., Crayton, A., Manzor, M., Mychalowych, A., Chase, J., Hammoud, S. S., Keegan, C. E., Maillard, I., Nandakumar, J.. 2021-07-29. Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline. https://doi.org/10.1101/2021.07.29.454392

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