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Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation.

ABSTRACT: Because spermatogonial stem cells (SSCs) are immortal by serial transplantation, SSC aging in intact testes is considered to be caused by a deteriorated microenvironment. Here, we report a cell-intrinsic mode of SSC aging by glycolysis activation. Using cultured SSCs, we found that aged SSCs proliferated more actively than young SSCs and showed enhanced glycolytic activity. Moreover, they remained euploid and exhibited stable androgenetic imprinting patterns with robust SSC activity despite having shortened telomeres. Aged SSCs showed increased Wnt7b expression, which was associated with decreased Polycomb complex 2 activity. Our results suggest that aberrant Wnt7b expression activated c-jun N-terminal kinase (JNK), which down-regulated mitochondria numbers by suppressing Ppargc1a Down-regulation of Ppargc1a probably decreased reactive oxygen species and enhanced glycolysis. Analyses of the Klotho-deficient aging mouse model and 2-y-old aged rats confirmed JNK hyperactivation and increased glycolysis. Therefore, not only microenvironment but also intrinsic activation of JNK-mediated glycolysis contributes to SSC aging.

SUBMITTER: Kanatsu-Shinohara M

PROVIDER: S-EPMC6697785 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation.

Kanatsu-Shinohara Mito M Yamamoto Takuya T Toh Hidehiro H Kazuki Yasuhiro Y Kazuki Kanako K Imoto Junichi J Ikeo Kazuho K Oshima Motohiko M Shirahige Katsuhiko K Iwama Atsushi A Nabeshima Yoichi Y Sasaki Hiroyuki H Shinohara Takashi T

Proceedings of the National Academy of Sciences of the United States of America 20190729 33

Because spermatogonial stem cells (SSCs) are immortal by serial transplantation, SSC aging in intact testes is considered to be caused by a deteriorated microenvironment. Here, we report a cell-intrinsic mode of SSC aging by glycolysis activation. Using cultured SSCs, we found that aged SSCs proliferated more actively than young SSCs and showed enhanced glycolytic activity. Moreover, they remained euploid and exhibited stable androgenetic imprinting patterns with robust SSC activity despite havi ...[more]

PMID: 31358627

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Project description:Insight into mechanisms controlling gene expression in the spermatogonial stem cell (SSC) will improve our understanding of the processes regulating spermatogenesis and aid in treating problems associated with male infertility. In this study we explored the global gene expression profiles of glial cell line-derived neurotrophic factor (GDNF) regulated transcription factors, Ets variant gene 5 (Etv5), B-cell CLL/lymphoma 6, member B (Bcl6b) and POU domain, class-3 transcription factor-1 (Pou3f1). We reasoned that these three factors may function as a core-set of transcription factors, regulating genes responsible for maintaining the SSC population. Using transient short-interfering RNA oligonucleotides (siRNA) to individually target Etv5, Bcl6b and Pou3f1 within mouse SSC cultures, we examined changes to the global gene expression profiles associated with these transcription factors. While there were only modest overlaps in the target genes regulated by the three factors, ETV5 was found to be a critical downstream regulator of GDNF signaling that mediated the expression of several known SSC self-renewal related genes including, Bcl6b and LIM homeobox 1 (Lhx1). Notably, ETV5 was identified as a regulator of Brachyury and CXC chemokine Receptor, type 4 (Cxcr4), and we show that ETV5 binding to the Brachyury gene promoter region is associated with an active state of transcription. Moreover, in vivo transplantation of SSCs following silencing of Brachyury significantly reduced the number of donor cell-derived colonies formed within recipient mouse testes. These results suggest Brachury is of biological importance, and functions as part of GDNF/ETV5 signaling to promote self-renewal of mouse SSCs cultured in vitro. Microarray gene expression analysis was conducted with Affymetrix Mouse 430 2.0 GeneChips (Affymetrix Inc.).Following with gene knockdown, total RNA from spermatogonial stem cells was converted to cDNA. There are total 16 samples (Four groups and four samples per group) Negative control (N), Bcl6b Knockdown (B), Etv5 knockdown (E), and Pou3f1 knockdown (O), respectively.

Dataset Information

Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation.

Publications

Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation.

Similar Datasets

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