TGF-β and Insulin Signaling Regulate Reproductive Aging Via Oocyte and Germline Quality Maintenance

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2010 Oct 16

PMID 20946987

Citations 153

Authors

Shijing Luo

Gunnar A Kleemann

Jasmine M Ashraf

Wendy M Shaw

Coleen T Murphy

Affiliations

Soon will be listed here.

Abstract

Reproductive cessation is perhaps the earliest aging phenotype that humans experience. Similarly, reproduction of Caenorhabditis elegans ceases in mid-adulthood. Although somatic aging has been studied in both worms and humans, mechanisms regulating reproductive aging are not yet understood. Here, we show that TGF-β Sma/Mab and Insulin/IGF-1 signaling regulate C. elegans reproductive aging by modulating multiple aspects of the reproductive process, including embryo integrity, oocyte fertilizability, chromosome segregation fidelity, DNA damage resistance, and oocyte and germline morphology. TGF-β activity regulates reproductive span and germline/oocyte quality noncell-autonomously and is temporally and transcriptionally separable from its regulation of growth. Chromosome segregation, cell cycle, and DNA damage response genes are upregulated in TGF-β mutant oocytes, decline in aged mammalian oocytes, and are critical for oocyte quality maintenance. Our data suggest that C. elegans and humans share many aspects of reproductive aging, including the correlation between reproductive aging and declining oocyte quality and mechanisms determining oocyte quality.

Citing Articles

Preconception exposure to perfluorooctanesulfonic acid (PFOS) and perfluorobutanesulfonic acid (PFBS) impaired reproduction via insulin/insulin-like growth factor signaling pathway without effects on the second generation in .

Li S, Yue Y, Qian Z, Teng Z, Clark J, Timme-Laragy A Toxicol Rep. 2025; 14:101966.

PMID: 40066201 PMC: 11891744. DOI: 10.1016/j.toxrep.2025.101966.

Menopause mysteries: the exosome-inflammation connection.

Sultania A, Brahadeeswaran S, Kolasseri A, Jayanthi S, Tamizhselvi R J Ovarian Res. 2025; 18(1):12.

PMID: 39849635 PMC: 11756133. DOI: 10.1186/s13048-025-01591-9.

Non-autonomous insulin signaling delays mitotic progression in C. elegans germline stem and progenitor cells.

Cheng E, Lu R, Gerhold A PLoS Genet. 2024; 20(12):e1011351.

PMID: 39715269 PMC: 11706408. DOI: 10.1371/journal.pgen.1011351.

The role of Sertoli cell-derived miR-143-3p in male fertility declines with age.

Liang J, Mei J, Chen D, Xiao Z, Hu M, Wei S Mol Ther Nucleic Acids. 2024; 35(4):102369.

PMID: 39640010 PMC: 11617286. DOI: 10.1016/j.omtn.2024.102369.

Adult single-nucleus neuronal transcriptomes of insulin signaling mutants reveal regulators of behavior and learning.

St Ange J, Weng Y, Kaletsky R, Stevenson M, Moore R, Zhou S Cell Genom. 2024; 4(12):100720.

PMID: 39637862 PMC: 11701262. DOI: 10.1016/j.xgen.2024.100720.

References

Tang L, Machacek T, Mamnun Y, Penkner A, Gloggnitzer J, Wegrostek C . Mutations in Caenorhabditis elegans him-19 show meiotic defects that worsen with age. Mol Biol Cell. 2010; 21(6):885-96. PMC: 2836969. DOI: 10.1091/mbc.e09-09-0811. View

Suh Y, Atzmon G, Cho M, Hwang D, Liu B, Leahy D . Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A. 2008; 105(9):3438-42. PMC: 2265137. DOI: 10.1073/pnas.0705467105. View

Liang J, Lints R, Foehr M, Tokarz R, Yu L, Emmons S . The Caenorhabditis elegans schnurri homolog sma-9 mediates stage- and cell type-specific responses to DBL-1 BMP-related signaling. Development. 2003; 130(26):6453-64. DOI: 10.1242/dev.00863. View

Rubio C, Simon C, Vidal F, Rodrigo L, Pehlivan T, Remohi J . Chromosomal abnormalities and embryo development in recurrent miscarriage couples. Hum Reprod. 2003; 18(1):182-8. DOI: 10.1093/humrep/deg015. View

Jud M, Razelun J, Bickel J, Czerwinski M, Schisa J . Conservation of large foci formation in arrested oocytes of Caenorhabditis nematodes. Dev Genes Evol. 2007; 217(3):221-6. DOI: 10.1007/s00427-006-0130-3. View

Knight P, Glister C . TGF-beta superfamily members and ovarian follicle development. Reproduction. 2006; 132(2):191-206. DOI: 10.1530/rep.1.01074. View

Andux S, Ellis R . Apoptosis maintains oocyte quality in aging Caenorhabditis elegans females. PLoS Genet. 2008; 4(12):e1000295. PMC: 2585808. DOI: 10.1371/journal.pgen.1000295. View

Nimmo R, Slack F . An elegant miRror: microRNAs in stem cells, developmental timing and cancer. Chromosoma. 2009; 118(4):405-18. PMC: 4322900. DOI: 10.1007/s00412-009-0210-z. View

Wang J, Tokarz R, Savage-Dunn C . The expression of TGFbeta signal transducers in the hypodermis regulates body size in C. elegans. Development. 2002; 129(21):4989-98. DOI: 10.1242/dev.129.21.4989. View

10.

Apfeld J, Kenyon C . Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span. Cell. 1998; 95(2):199-210. DOI: 10.1016/s0092-8674(00)81751-1. View

11.

Libina N, Berman J, Kenyon C . Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell. 2003; 115(4):489-502. DOI: 10.1016/s0092-8674(03)00889-4. View

12.

Ghazi A, Henis-Korenblit S, Kenyon C . A transcription elongation factor that links signals from the reproductive system to lifespan extension in Caenorhabditis elegans. PLoS Genet. 2009; 5(9):e1000639. PMC: 2729384. DOI: 10.1371/journal.pgen.1000639. View

13.

Murphy C, McCarroll S, Bargmann C, Fraser A, Kamath R, Ahringer J . Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature. 2003; 424(6946):277-83. DOI: 10.1038/nature01789. View

14.

Liang J, Yu L, Yin J, Savage-Dunn C . Transcriptional repressor and activator activities of SMA-9 contribute differentially to BMP-related signaling outputs. Dev Biol. 2007; 305(2):714-25. DOI: 10.1016/j.ydbio.2007.02.038. View

15.

Tokunaga C . The effects of low temperature and aging on nondisjunction in Drosophila. Genetics. 1970; 65(1):75-94. PMC: 1212434. DOI: 10.1093/genetics/65.1.75. View

16.

Hodgkin J, Horvitz H, Brenner S . Nondisjunction Mutants of the Nematode CAENORHABDITIS ELEGANS. Genetics. 1979; 91(1):67-94. PMC: 1213932. DOI: 10.1093/genetics/91.1.67. View

17.

Massague J . How cells read TGF-beta signals. Nat Rev Mol Cell Biol. 2001; 1(3):169-78. DOI: 10.1038/35043051. View

18.

Angelo G, Van Gilst M . Starvation protects germline stem cells and extends reproductive longevity in C. elegans. Science. 2009; 326(5955):954-8. DOI: 10.1126/science.1178343. View

19.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

20.

Miller M . Sperm and oocyte isolation methods for biochemical and proteomic analysis. Methods Mol Biol. 2006; 351:193-201. DOI: 10.1385/1-59745-151-7:193. View