Bibliographic record
Abstract
Two genes that have established roles in the regulation of cell survival are telomerase reverse transcriptase (Tert) and the nicotinamide adenine dinucleotide-dependent protein deactylase Sirt1. However, the relative importance of these genes to the survival of stem cells, and the regulation of expression of these genes in stem cells, has yet to be thoroughly established. We now show that telomerase suppression in quiescent male primordial germ cells (PGCs) from murine embryos is accompanied by a decrease in expression of TERT. Telomerase activity was detected in quiescent PGCs from transgenic embryos, that constitutively express TERT, demonstrating that re-activation of TERT expression is sufficient to restore telomerase activity in these cells and implying that TERT expression is an important mechanism of telomerase regulation in PGCs. These results also demonstrate that TERT per se does not affect proliferation or development of PGCs in mammals, Sirt1, a member of the sirtuin family of proteins, orthologous to the yeast Sir2, has important physiological roles in regulating glucose metabolism. We have now performed a detailed analysis of the molecular and functional effects of Sirt1 deficiency in the germ line of Sirt1 knock-out (-/-) mice. We find that Sirt1 deficiency markedly attenuates spermatogenesis, but not oogenesis. Microarray analysis in Sirt1 deficient testis revealed dysregulated expression of 85 genes, which were enriched (P<0.05) for genes involved in spermatogenesis and protein sumoylation. To assess the function of Sirt1 deficient germ cells, we compared the efficiency of generating embryos and offspring in in vitro fertilization (IVF) experiments using gametes from Sirt1 deficient mice. While viable animals were derived in all experiments, the efficiency of producing both 2-cell zygotes and viable offspring was diminished when IVF was performed with Sirt1-/- gametes. Using short hairpin RNAs, we found that inhibition of Sirt1 in immortalized human cells enhanced cell growth under normal and nutrient limiting conditions. Hematopoietic stem cells, which were shown to express Sirt1, showed increased growth capacity and decreased dependency on growth factors when the Sirt1 gene was deleted. These data support an important role for Sirt1 in spermatogenesis, including spermatogenic stem cells, as well as germ cell function, but also demonstrate that in certain cell lineages, Sirt1 can act as a growth suppressor.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".