Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Soma-to-germline RNA communication

Nature Reviews Genetics volume 23, pages 73–88 (2022)Cite this article

Subjects

Abstract

More than a century ago, August Weissman defined a distinction between the germline (responsible for propagating heritable information from generation to generation) and the perishable soma. A central motivation for this distinction was to argue against the inheritance of acquired characters, as the germline was partly defined by its protection from external conditions. However, recent decades have seen an explosion of studies documenting the intergenerational and transgenerational effects of environmental conditions, forcing a re-evaluation of how external signals are sensed by, or communicated to, the germline epigenome. Here, motivated by the centrality of small RNAs in paradigms of epigenetic inheritance, we review across species the myriad examples of intercellular RNA trafficking from nurse cells or somatic tissues to developing gametes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Germline niche cells.
Fig. 2: Dead-end germline products.
Fig. 3: Vesicle trafficking from dedicated reproductive support tissues.
Fig. 4: Systemic RNA spread.
Fig. 5: Environmental control of the mammalian sperm epigenome.

Similar content being viewed by others

References

  1. Boskovic, A. & Rando, O. J. Transgenerational epigenetic inheritance. Annu. Rev. Genet. 52, 21–41 (2018).

    Article  CAS  PubMed  Google Scholar 

  2. Heard, E. & Martienssen, R. A. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157, 95–109 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kawashima, T. & Berger, F. Epigenetic reprogramming in plant sexual reproduction. Nat. Rev. Genet. 15, 613–624 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. Hackett, J. A. & Surani, M. A. Beyond DNA: programming and inheritance of parental methylomes. Cell 153, 737–739 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sharma, U. Paternal contributions to offspring health: role of sperm small RNAs in intergenerational transmission of epigenetic information. Front. Cell Dev. Biol. 7, 215 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Madhani, H. D. The frustrated gene: origins of eukaryotic gene expression. Cell 155, 744–749 (2013). An excellent overview of how the need to control transposons may have driven the complexity of gene regulatory mechanisms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ringrose, L. & Paro, R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu. Rev. Genet. 38, 413–443 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Eckersley-Maslin, M. A., Alda-Catalinas, C. & Reik, W. Dynamics of the epigenetic landscape during the maternal-to-zygotic transition. Nat. Rev. Mol. Cell Biol. 19, 436–450 (2018).

    Article  CAS  PubMed  Google Scholar 

  9. Hackett, J. A. & Surani, M. A. DNA methylation dynamics during the mammalian life cycle. Phil. Trans. R. Soc. B 368, 20110328 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33, 245–254 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Jirtle, R. L. & Skinner, M. K. Environmental epigenomics and disease susceptibility. Nat. Rev. Genet. 8, 253–262 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Galan, C., Krykbaeva, M. & Rando, O. J. Early life lessons: the lasting effects of germline epigenetic information on organismal development. Mol. Metab. 38, 100924 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Rando, O. J. Daddy issues: paternal effects on phenotype. Cell 151, 702–708 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Drummond-Barbosa, D. & Spradling, A. C. Stem cells and their progeny respond to nutritional changes during Drosophila oogenesis. Dev. Biol. 231, 265–278 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. McLeod, C. J., Wang, L., Wong, C. & Jones, D. L. Stem cell dynamics in response to nutrient availability. Curr. Biol. 20, 2100–2105 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. LaFever, L. & Drummond-Barbosa, D. Direct control of germline stem cell division and cyst growth by neural insulin in Drosophila. Science 309, 1071–1073 (2005). Demonstrates the role of systemic factors in control of germ cell production.

    Article  CAS  PubMed  Google Scholar 

  17. Tadokoro, Y., Yomogida, K., Ohta, H., Tohda, A. & Nishimune, Y. Homeostatic regulation of germinal stem cell proliferation by the GDNF/FSH pathway. Mech. Dev. 113, 29–39 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. De La Fuente, R. & Eppig, J. J. Transcriptional activity of the mouse oocyte genome: companion granulosa cells modulate transcription and chromatin remodeling. Dev. Biol. 229, 224–236 (2001).

    Article  Google Scholar 

  19. Haig, D. Weismann Rules! OK? Epigenetics and the Lamarckian temptation. Biol. Philos. 22, 415–428 (2007).

    Article  Google Scholar 

  20. Spradling, A. in The Development of Drosophila Melanogaster (eds Bate, M. & Arias, A. M.) 1–70 (Cold Spring Harbor Laboratory Press, 1993).

  21. Kloc, M., Bilinski, S. & Etkin, L. D. The Balbiani body and germ cell determinants: 150 years later. Curr. Top. Dev. Biol. 59, 1–36 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Cox, R. T. & Spradling, A. C. A Balbiani body and the fusome mediate mitochondrial inheritance during Drosophila oogenesis. Development 130, 1579–1590 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Tworzydlo, W., Sekula, M. & Bilinski, S. M. Transmission of functional, wild-type mitochondria and the fittest mtDNA to the next generation: bottleneck phenomenon, Balbiani body, and mitophagy. Genes 11, 104 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  24. Orr-Weaver, T. L. When bigger is better: the role of polyploidy in organogenesis. Trends Genet. 31, 307–315 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Strome, S. & Lehmann, R. Germ versus soma decisions: lessons from flies and worms. Science 316, 392–393 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Malone, C. D. et al. Specialized piRNA pathways act in germline and somatic tissues of the Drosophila ovary. Cell 137, 522–535 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tiwari, B. et al. Retrotransposons mimic germ plasm determinants to promote transgenerational inheritance. Curr. Biol. 27, 3010–3016.e3 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang, L., Dou, K., Moon, S., Tan, F. J. & Zhang, Z. Z. Hijacking oogenesis enables massive propagation of LINE and retroviral transposons. Cell 174, 1082–1094.e12 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128, 1089–1103 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Gunawardane, L. S. et al. A slicer-mediated mechanism for repeat-associated siRNA 5′ end formation in Drosophila. Science 315, 1587–1590 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Vagin, V. V. et al. A distinct small RNA pathway silences selfish genetic elements in the germline. Science 313, 320–324 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Klattenhoff, C. & Theurkauf, W. Biogenesis and germline functions of piRNAs. Development 135, 3–9 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Pepling, M. E., Wilhelm, J. E., O’Hara, A. L., Gephardt, G. W. & Spradling, A. C. Mouse oocytes within germ cell cysts and primordial follicles contain a Balbiani body. Proc. Natl Acad. Sci. USA 104, 187–192 (2007). Discovery of Balbiani bodies in mouse oocytes.

    Article  CAS  PubMed  Google Scholar 

  34. Lei, L. & Spradling, A. C. Mouse oocytes differentiate through organelle enrichment from sister cyst germ cells. Science 352, 95–99 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wolke, U., Jezuit, E. A. & Priess, J. R. Actin-dependent cytoplasmic streaming in C. elegans oogenesis. Development 134, 2227–2236 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Raiders, S. A., Eastwood, M. D., Bacher, M. & Priess, J. R. Binucleate germ cells in Caenorhabditis elegans are removed by physiological apoptosis. PLoS Genet. 14, e1007417 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Braun, R. E., Behringer, R. R., Peschon, J. J., Brinster, R. L. & Palmiter, R. D. Genetically haploid spermatids are phenotypically diploid. Nature 337, 373–376 (1989). Demonstration of cytoplasmic RNA sharing between haploid sperm in mice.

    Article  CAS  PubMed  Google Scholar 

  38. Ventela, S., Toppari, J. & Parvinen, M. Intercellular organelle traffic through cytoplasmic bridges in early spermatids of the rat: mechanisms of haploid gene product sharing. Mol. Biol. Cell 14, 2768–2780 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Veron, N. et al. Retention of gene products in syncytial spermatids promotes non-Mendelian inheritance as revealed by the T complex responder. Genes Dev. 23, 2705–2710 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bhutani, K. et al. Widespread haploid-biased gene expression enables sperm-level natural selection. Science 371, eabb1723 (2021). Mammalian sperm retain a subset of haploid-expressed mRNAs.

    Article  CAS  PubMed  Google Scholar 

  41. Dodson, A. E. & Kennedy, S. Phase separation in germ cells and development. Dev. Cell 55, 4–17 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Allan, D. J., Harmon, B. V. & Roberts, S. A. Spermatogonial apoptosis has three morphologically recognizable phases and shows no circadian rhythm during normal spermatogenesis in the rat. Cell Prolif. 25, 241–250 (1992).

    Article  CAS  PubMed  Google Scholar 

  43. Shaha, C., Tripathi, R. & Mishra, D. P. Male germ cell apoptosis: regulation and biology. Phil. Trans. R. Soc. B 365, 1501–1515 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. McCue, A. D., Cresti, M., Feijo, J. A. & Slotkin, R. K. Cytoplasmic connection of sperm cells to the pollen vegetative cell nucleus: potential roles of the male germ unit revisited. J. Exp. Bot. 62, 1621–1631 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Slotkin, R. K. et al. Epigenetic reprogramming and small RNA silencing of transposable elements in pollen. Cell 136, 461–472 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Martinez, G., Panda, K., Kohler, C. & Slotkin, R. K. Silencing in sperm cells is directed by RNA movement from the surrounding nurse cell. Nat. Plants 2, 16030 (2016). Demonstration of siRNA trafficking from vegetative cells to sperm cells in Arabidopsis.

    Article  CAS  PubMed  Google Scholar 

  47. Grant-Downton, R. et al. Artificial microRNAs reveal cell-specific differences in small RNA activity in pollen. Curr. Biol. 23, R599–R601 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Ibarra, C. A. et al. Active DNA demethylation in plant companion cells reinforces transposon methylation in gametes. Science 337, 1360–1364 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Erdmann, R. M. et al. Molecular movement in the Arabidopsis thaliana female gametophyte. Plant. Reprod. 30, 141–146 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Prescott, D. M. The DNA of ciliated protozoa. Microbiol. Rev. 58, 233–267 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tucker, J. B., Beisson, J., Roche, D. L. & Cohen, J. Microtubules and control of macronuclear ‘amitosis’ in Paramecium. J. Cell Sci. 44, 135–151 (1980).

    Article  CAS  PubMed  Google Scholar 

  52. Bracht, J. R. et al. Genomes on the edge: programmed genome instability in ciliates. Cell 152, 406–416 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Parfrey, L. W., Lahr, D. J., Knoll, A. H. & Katz, L. A. Estimating the timing of early eukaryotic diversification with multigene molecular clocks. Proc. Natl Acad. Sci. USA 108, 13624–13629 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chalker, D. L. & Yao, M. C. Nongenic, bidirectional transcription precedes and may promote developmental DNA deletion in Tetrahymena thermophila. Genes Dev. 15, 1287–1298 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lepere, G., Betermier, M., Meyer, E. & Duharcourt, S. Maternal noncoding transcripts antagonize the targeting of DNA elimination by scanRNAs in Paramecium tetraurelia. Genes Dev. 22, 1501–1512 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Fang, W., Wang, X., Bracht, J. R., Nowacki, M. & Landweber, L. F. Piwi-interacting RNAs protect DNA against loss during Oxytricha genome rearrangement. Cell 151, 1243–1255 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Orgebin-Crist, M. C. Sperm maturation in rabbit epididymis. Nature 216, 816–818 (1967). Epididymal transit is required for the acquisition of sperm motility and fertility in mammals.

    Article  CAS  PubMed  Google Scholar 

  58. Bedford, J. M. Effects of duct ligation on the fertilizing ability of spermatozoa from different regions of the rabbit epididymis. J. Exp. Zool. 166, 271–281 (1967).

    Article  CAS  PubMed  Google Scholar 

  59. Gervasi, M. G. & Visconti, P. E. Molecular changes and signaling events occurring in spermatozoa during epididymal maturation. Andrology 5, 204–218 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Domeniconi, R. F., Souza, A. C., Xu, B., Washington, A. M. & Hinton, B. T. Is the epididymis a series of organs placed side by side? Biol. Reprod. 95, 10 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Johnston, D. S. et al. The mouse epididymal transcriptome: transcriptional profiling of segmental gene expression in the epididymis. Biol. Reprod. 73, 404–413 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Frenette, G. & Sullivan, R. Prostasome-like particles are involved in the transfer of P25b from the bovine epididymal fluid to the sperm surface. Mol. Reprod. Dev. 59, 115–121 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Sullivan, R., Frenette, G. & Girouard, J. Epididymosomes are involved in the acquisition of new sperm proteins during epididymal transit. Asian J. Androl. 9, 483–491 (2007). Vesicles released by the eididymis fuse with sperm to deliver proteins important for fertility in mammals.

    Article  CAS  PubMed  Google Scholar 

  64. Sullivan, R. & Saez, F. Epididymosomes, prostasomes, and liposomes: their roles in mammalian male reproductive physiology. Reproduction 146, R21–R35 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Krapf, D. et al. cSrc is necessary for epididymal development and is incorporated into sperm during epididymal transit. Dev. Biol. 369, 43–53 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tamessar, C. T. et al. Roles of male reproductive tract extracellular vesicles in reproduction. Am. J. Reprod. Immunol. 85, e13338 (2021).

    Article  PubMed  Google Scholar 

  67. Peng, H. et al. A novel class of tRNA-derived small RNAs extremely enriched in mature mouse sperm. Cell Res. 22, 1609–1612 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nixon, B. et al. The microRNA signature of mouse spermatozoa is substantially modified during epididymal maturation. Biol. Reprod. 93, 91 (2015).

    Article  PubMed  Google Scholar 

  69. Sharma, U. et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351, 391–396 (2016). Survery of small RNA dynamics during post-testicular maturation of mammalian sperm.

    Article  CAS  PubMed  Google Scholar 

  70. Sellem, E. et al. Dynamics of cattle sperm sncRNAs during maturation, from testis to ejaculated sperm. Epigenetics Chromatin 14, 24 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Johnson, G. D. et al. Cleavage of rRNA ensures translational cessation in sperm at fertilization. Mol. Hum. Reprod. 17, 721–726 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gou, L. T. et al. Pachytene piRNAs instruct massive mRNA elimination during late spermiogenesis. Cell Res. 24, 680–700 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Goh, W. S. et al. piRNA-directed cleavage of meiotic transcripts regulates spermatogenesis. Genes Dev. 29, 1032–1044 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Zhang, P. et al. MIWI and piRNA-mediated cleavage of messenger RNAs in mouse testes. Cell Res. 25, 193–207 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Reilly, J. N. et al. Characterisation of mouse epididymosomes reveals a complex profile of microRNAs and a potential mechanism for modification of the sperm epigenome. Sci. Rep. 6, 31794 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Sharma, U. et al. Small RNAs are trafficked from the epididymis to developing mammalian sperm. Dev. Cell 46, 481–494.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Belleannee, C., Calvo, E., Caballero, J. & Sullivan, R. Epididymosomes convey different repertoires of microRNAs throughout the bovine epididymis. Biol. Reprod. 89, 30 (2013).

    Article  PubMed  Google Scholar 

  78. Twenter, H. et al. Transfer of microRNAs from epididymal epithelium to equine spermatozoa. J. Equine Vet. Sci. 87, 102841 (2020).

    Article  PubMed  Google Scholar 

  79. Rompala, G. R., Ferguson, C. & Homanics, G. E. Coincubation of sperm with epididymal extracellular vesicle preparations from chronic intermittent ethanol-treated mice is sufficient to impart anxiety-like and ethanol-induced behaviors to adult progeny. Alcohol 87, 111–120 (2020). Functional role for epididymosomal RNA delivery to sperm in control of offspring phenotype in mice is shown.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chan, J. C. et al. Reproductive tract extracellular vesicles are sufficient to transmit intergenerational stress and program neurodevelopment. Nat. Commun. 11, 1499 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Capra, E. & Lange-Consiglio, A. The biological function of extracellular vesicles during fertilization, early embryo-maternal crosstalk and their involvement in reproduction: review and overview. Biomolecules 10, 1510 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  82. Pons-Rejraji, H. et al. Prostasomes: inhibitors of capacitation and modulators of cellular signalling in human sperm. Int. J. Androl. 34, 568–580 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Chen, X. et al. Early cleavage of preimplantation embryos is regulated by tRNA(Gln-TTG)-derived small RNAs present in mature spermatozoa. J. Biol. Chem. 295, 10885–10900 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Fabiani, R., Johansson, L., Lundkvist, O. & Ronquist, G. Enhanced recruitment of motile spermatozoa by prostasome inclusion in swim-up medium. Hum. Reprod. 9, 1485–1489 (1994).

    Article  CAS  PubMed  Google Scholar 

  85. Park, K. H. et al. Ca2+ signaling tools acquired from prostasomes are required for progesterone-induced sperm motility. Sci. Signal. 4, ra31 (2011).

    Article  PubMed  Google Scholar 

  86. Corrigan, L. et al. BMP-regulated exosomes from Drosophila male reproductive glands reprogram female behavior. J. Cell Biol. 206, 671–688 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hopkins, B. R. et al. BMP signaling inhibition in Drosophila secondary cells remodels the seminal proteome and self and rival ejaculate functions. Proc. Natl Acad. Sci. USA 116, 24719–24728 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Buccione, R., Schroeder, A. C. & Eppig, J. J. Interactions between somatic cells and germ cells throughout mammalian oogenesis. Biol. Reprod. 43, 543–547 (1990).

    Article  CAS  PubMed  Google Scholar 

  89. Su, Y. Q., Sugiura, K. & Eppig, J. J. Mouse oocyte control of granulosa cell development and function: paracrine regulation of cumulus cell metabolism. Semin. Reprod. Med. 27, 32–42 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Albertini, D. F., Combelles, C. M., Benecchi, E. & Carabatsos, M. J. Cellular basis for paracrine regulation of ovarian follicle development. Reproduction 121, 647–653 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Clarke, H. J. Regulation of germ cell development by intercellular signaling in the mammalian ovarian follicle. Wiley Interdiscip. Rev. Dev. Biol. 7, e294 (2018).

    Article  Google Scholar 

  92. Coticchio, G. et al. Oocyte maturation: gamete-somatic cells interactions, meiotic resumption, cytoskeletal dynamics and cytoplasmic reorganization. Hum. Reprod. update 21, 427–454 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. Macaulay, A. D. et al. The gametic synapse: RNA transfer to the bovine oocyte. Biol. Reprod. 91, 90 (2014).

    Article  PubMed  Google Scholar 

  94. Macaulay, A. D. et al. Cumulus cell transcripts transit to the bovine oocyte in preparation for maturation. Biol. Reprod. 94, 16 (2016). Shows RNA trafficking from granulosa cells to mammalian oocytes.

    Article  PubMed  Google Scholar 

  95. Whitten, S. J. & Miller, M. A. The role of gap junctions in Caenorhabditis elegans oocyte maturation and fertilization. Dev. Biol. 301, 432–446 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Li, C. et al. Collapse of germline piRNAs in the absence of Argonaute3 reveals somatic piRNAs in flies. Cell 137, 509–521 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Pelisson, A. et al. Gypsy transposition correlates with the production of a retroviral envelope-like protein under the tissue-specific control of the Drosophila flamenco gene. EMBO J. 13, 4401–4411 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Song, S. U., Kurkulos, M., Boeke, J. D. & Corces, V. G. Infection of the germ line by retroviral particles produced in the follicle cells: a possible mechanism for the mobilization of the gypsy retroelement of Drosophila. Development 124, 2789–2798 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Machtinger, R., Laurent, L. C. & Baccarelli, A. A. Extracellular vesicles: roles in gamete maturation, fertilization and embryo implantation. Hum. Reprod. Update 22, 182–193 (2016).

    CAS  PubMed  Google Scholar 

  100. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998). Describes the discovery of RNAi.

    Article  CAS  PubMed  Google Scholar 

  101. Grishok, A., Tabara, H. & Mello, C. C. Genetic requirements for inheritance of RNAi in C. elegans. Science 287, 2494–2497 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Alcazar, R. M., Lin, R. & Fire, A. Z. Transmission dynamics of heritable silencing induced by double-stranded RNA in Caenorhabditis elegans. Genetics 180, 1275–1288 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Timmons, L. & Fire, A. Specific interference by ingested dsRNA. Nature 395, 854 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Winston, W. M., Molodowitch, C. & Hunter, C. P. Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Science 295, 2456–2459 (2002). Genetic identification of factors required for systemic RNA trafficking in worms.

    Article  CAS  PubMed  Google Scholar 

  105. Marre, J., Traver, E. C. & Jose, A. M. Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 113, 12496–12501 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Devanapally, S., Ravikumar, S. & Jose, A. M. Double-stranded RNA made in C. elegans neurons can enter the germline and cause transgenerational gene silencing. Proc. Natl Acad. Sci. USA 112, 2133–2138 (2015). Demonstration of functional RNA trafficking from neurons to germ line in worms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Posner, R. et al. Neuronal small RNAs control behavior transgenerationally. Cell 177, 1814–1826.e15 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Tijsterman, M., May, R. C., Simmer, F., Okihara, K. L. & Plasterk, R. H. Genes required for systemic RNA interference in Caenorhabditis elegans. Curr. Biol. 14, 111–116 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Moore, R. S., Kaletsky, R. & Murphy, C. T. Piwi/PRG-1 argonaute and TGF-beta mediate transgenerational learned pathogenic avoidance. Cell 177, 1827–1841.e12 (2019). C. elegans behaviours are transmitted transgenerationally via small RNAs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kaletsky, R. et al. C. elegans interprets bacterial non-coding RNAs to learn pathogenic avoidance. Nature 586, 445–451 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Voinnet, O. & Baulcombe, D. C. Systemic signalling in gene silencing. Nature 389, 553 (1997).

    Article  CAS  PubMed  Google Scholar 

  112. Palauqui, J. C., Elmayan, T., Pollien, J. M. & Vaucheret, H. Systemic acquired silencing: transgene-specific post-transcriptional silencing is transmitted by grafting from silenced stocks to non-silenced scions. EMBO J. 16, 4738–4745 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Voinnet, O., Vain, P., Angell, S. & Baulcombe, D. C. Systemic spread of sequence-specific transgene RNA degradation in plants is initiated by localized introduction of ectopic promoterless DNA. Cell 95, 177–187 (1998). Describes systemic RNA trafficking in plants.

    Article  CAS  PubMed  Google Scholar 

  114. Pant, B. D., Buhtz, A., Kehr, J. & Scheible, W. R. MicroRNA399 is a long-distance signal for the regulation of plant phosphate homeostasis. Plant J. 53, 731–738 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chitwood, D. H. et al. Pattern formation via small RNA mobility. Genes Dev. 23, 549–554 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Melnyk, C. W., Molnar, A. & Baulcombe, D. C. Intercellular and systemic movement of RNA silencing signals. EMBO J. 30, 3553–3563 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Melnyk, C. W., Molnar, A., Bassett, A. & Baulcombe, D. C. Mobile 24 nt small RNAs direct transcriptional gene silencing in the root meristems of Arabidopsis thaliana. Curr. Biol. B 21, 1678–1683 (2011).

    Article  CAS  Google Scholar 

  118. Molnar, A. et al. Small silencing RNAs in plants are mobile and direct epigenetic modification in recipient cells. Science 328, 872–875 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Tamiru, M., Hardcastle, T. J. & Lewsey, M. G. Regulation of genome-wide DNA methylation by mobile small RNAs. N. Phytol. 217, 540–546 (2018).

    Article  CAS  Google Scholar 

  120. Thieme, C. J. et al. Endogenous Arabidopsis messenger RNAs transported to distant tissues. Nat. Plants 1, 15025 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Zhang, W. et al. tRNA-related sequences trigger systemic mRNA transport in plants. Plant Cell 28, 1237–1249 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Brosnan, C. A. & Voinnet, O. Cell-to-cell and long-distance siRNA movement in plants: mechanisms and biological implications. Curr. Opin. Plant Biol. 14, 580–587 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Sarkies, P. & Miska, E. A. Small RNAs break out: the molecular cell biology of mobile small RNAs. Nat. Rev. Mol. Cell Biol. 15, 525–535 (2014).

    Article  CAS  PubMed  Google Scholar 

  124. Devers, E. A. et al. Movement and differential consumption of short interfering RNA duplexes underlie mobile RNA interference. Nat. Plants 6, 789–799 (2020).

    Article  CAS  PubMed  Google Scholar 

  125. Schmidt, A., Schmid, M. W. & Grossniklaus, U. Plant germline formation: common concepts and developmental flexibility in sexual and asexual reproduction. Development 142, 229–241 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Zhang, W. et al. Graft-transmissible movement of inverted-repeat-induced siRNA signals into flowers. Plant J. 80, 106–121 (2014).

    Article  CAS  PubMed  Google Scholar 

  127. Kasai, A., Bai, S., Hojo, H. & Harada, T. Epigenome editing of potato by grafting using transgenic tobacco as siRNA donor. PLoS ONE 11, e0161729 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Virdi, K. S. et al. Arabidopsis MSH1 mutation alters the epigenome and produces heritable changes in plant growth. Nat. Commun. 6, 6386 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Kundariya, H. et al. MSH1-induced heritable enhanced growth vigor through grafting is associated with the RdDM pathway in plants. Nat. Commun. 11, 5343 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Cossetti, C. et al. Soma-to-germline transmission of RNA in mice xenografted with human tumour cells: possible transport by exosomes. PLoS ONE 9, e101629 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  131. O’Brien, E. A., Ensbey, K. S., Day, B. W., Baldock, P. A. & Barry, G. Direct evidence for transport of RNA from the mouse brain to the germline and offspring. BMC Biol. 18, 45 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Zhang, Y. et al. Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs. Nat. Cell Biol. 20, 535–540 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Rompala, G. R. et al. Heavy chronic intermittent ethanol exposure alters small noncoding RNAs in mouse sperm and epididymosomes. Front. Genet. 9, 32 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Yoshida, K. et al. ATF7-dependent epigenetic changes are required for the intergenerational effect of a paternal low-protein diet. Mol. Cell 78, 445–458.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  135. Nilsson, E. E., Maamar, M. B. & Skinner, M. K. Environmentally induced epigenetic transgenerational inheritance and the weismann barrier: the dawn of neo-Lamarckian theory. J. Dev. Biol. 8, 28 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  136. Janke, R., Dodson, A. E. & Rine, J. Metabolism and epigenetics. Annu. Rev. Cell Dev. Biol. 31, 473–496 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sharma, U. & Rando, O. J. Metabolic inputs into the epigenome. Cell Metab. 25, 544–558 (2017).

    Article  CAS  PubMed  Google Scholar 

  138. Padmanabhan, N. et al. Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development. Cell 155, 81–93 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Lismer, A. et al. Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring. Dev. Cell 56, 671–686.e6 (2021).

    Article  CAS  PubMed  Google Scholar 

  140. Watkins, A. J. et al. Paternal diet programs offspring health through sperm- and seminal plasma-specific pathways in mice. Proc. Natl Acad. Sci. USA 115, 10064–10069 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kimble, J. Alterations in cell lineage following laser ablation of cells in the somatic gonad of Caenorhabditis elegans. Dev. Biol. 87, 286–300 (1981).

    Article  CAS  PubMed  Google Scholar 

  142. Kimble, J. E. & White, J. G. On the control of germ cell development in Caenorhabditis elegans. Dev. Biol. 81, 208–219 (1981).

    Article  CAS  PubMed  Google Scholar 

  143. Hai, Y. et al. The roles and regulation of Sertoli cells in fate determinations of spermatogonial stem cells and spermatogenesis. Semin. Cell Dev. Biol. 29, 66–75 (2014).

    Article  CAS  PubMed  Google Scholar 

  144. Arteaga-Vazquez, M. A. & Chandler, V. L. Paramutation in maize: RNA mediated trans-generational gene silencing. Curr. Opin. Genet. Dev. 20, 156–163 (2010). Excellent review of paramutation, the first epigenetic inheritance paradigm characterized in detail.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Chen, Q. et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397–400 (2016).

    Article  CAS  PubMed  Google Scholar 

  146. Gapp, K. et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat. Neurosci. 17, 667–669 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sarker, G. et al. Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs. Proc. Natl Acad. Sci. USA 116, 10547–10556 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Wagner, K. D. et al. RNA induction and inheritance of epigenetic cardiac hypertrophy in the mouse. Dev. Cell 14, 962–969 (2008).

    Article  CAS  PubMed  Google Scholar 

  149. Grandjean, V. et al. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci. Rep. 5, 18193 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Rodgers, A. B., Morgan, C. P., Leu, N. A. & Bale, T. L. Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc. Natl Acad. Sci. USA 112, 13699–13704 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank V. Rinaldi and C. Galan for critical reading of the manuscript, and K. Slotkin and J. McCarrey for helpful discussions. This work was supported by Templeton Foundation Grant 61350 to O.J.R. and a Pew Biomedical Scholars Award to C.C.C.

Author information

Authors and Affiliations

  1. Departments of Genetics and Paediatrics, University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Colin C. Conine

  2. Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA

    Oliver J. Rando

Authors
  1. Colin C. Conine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver J. Rando
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors contributed to all aspects of the article.

Corresponding authors

Correspondence to Colin C. Conine or Oliver J. Rando.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Genetics thanks the reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Selfish genetic elements

DNA sequences that can move within a genome and generate multiple copies, often to the detriment of the host, most famously, transposons.

Balbiani body

A subcellular structure in oocytes comprising mitochondria, endoplasmic reticulum and Golgi membranes, and germ plasm RNAs and proteins.

Endo-replicate

To copy parts of the genome without mitosis, leading either to whole genome polyploidy or to selective amplification of specific genomic loci.

Argonautes

Effector proteins that bind to small RNAs such as short interfering RNAs, microRNAs and PIWI-interacting RNAs, and use these small RNAs to target homologous RNAs such as transposon RNAs.

Syncytium

A structure, often formed by cell fusion or nuclear division without cell division, in which multiple nuclei share the same cytoplasm.

Oolemma

The oocyte membrane.

RNA-directed DNA methylation (RdDM) pathway

A pathway in plants in which small RNAs direct cytosine methylation at genomic target sites.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Conine, C.C., Rando, O.J. Soma-to-germline RNA communication. Nat Rev Genet 23, 73–88 (2022). https://doi.org/10.1038/s41576-021-00412-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41576-021-00412-1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing