Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline
| Autor: | Saher Sue Hammoud, Aniela Crayton, Jacqueline Graniel, Peedikayil E. Thomas, Leolene J Carrington, Catherine E. Keegan, Joshua D Brandstadter, Jayakrishnan Nandakumar, Adrienne Niederriter Shami, James J. White, Kamlesh Bisht, Alina Moroz, Jennifer Chase, Frederick Allen, Ann Friedman, Eric Perkey, Ivan Maillard, Anna Mychalowych, Mariel Manzor, Ashley Vanderbeck |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Models Molecular Telomerase Somatic cell Health Toxicology and Mutagenesis Telomere-Binding Proteins Plant Science Biology medicine.disease_cause Biochemistry Genetics and Molecular Biology (miscellaneous) Dyskeratosis Congenita Germline Mice Structure-Activity Relationship medicine Animals Humans Amino Acid Sequence Research Articles Gene Editing Mice Knockout Mutation Sperm Count Ecology Lymphopoiesis Homozygote Bone marrow failure Shelterin medicine.disease Hematopoiesis Telomere Cell biology Fertility Germ Cells medicine.anatomical_structure Organ Specificity Knockout mouse Bone marrow CRISPR-Cas Systems Dyskeratosis congenita Research Article |
| Zdroj: | Life Science Alliance |
| Popis: | A TPP1 mutation known to cause telomere shortening and bone marrow failure in humans recapitulates telomere loss but results in severe germline defects in mice without impacting murine hematopoiesis. 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, frequently resulting in spontaneous bone marrow failure. A dyskeratosis congenita mutation in TPP1 (K170∆) that specifically compromises telomerase recruitment to telomeres is a valuable tool to evaluate telomerase-dependent telomere length maintenance in mice. We used CRISPR-Cas9 to generate a mouse knocked in for the equivalent of the TPP1 K170∆ mutation (TPP1 K82∆) and investigated both its hematopoietic and germline compartments in unprecedented detail. TPP1 K82∆ caused progressive telomere erosion with increasing generation number but did not induce steady-state hematopoietic defects. Strikingly, K82∆ caused mouse infertility, consistent with gross morphological defects in the testis and sperm, the appearance of dysfunctional seminiferous tubules, and a decrease in germ cells. Intriguingly, both TPP1 K82∆ mice and previously characterized telomerase knockout mice show no spontaneous bone marrow failure but rather succumb to infertility at steady-state. We speculate that telomere length maintenance contributes differently to the evolutionary fitness of humans and mice. |
| Databáze: | OpenAIRE |
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