Biology:Germline development

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Short description: How an animal develops its sexual-reproduction cells

In developmental biology, the cells that give rise to the gametes are often set aside during embryonic cleavage. During development, these cells will differentiate into primordial germ cells, migrate to the location of the gonad, and form the germline of the animal.

Creation of germ plasm and primordial germ cells

Cleavage in most animals segregates cells containing germ plasm from other cells. The germ plasm effectively turns off gene expression to render the genome of the cell inert. Cells expressing germ plasm become primordial germ cells (PGCs) which will then give rise to the gametes. The germ line development in mammals, on the other hand, occurs by induction and not by an endogenous germ plasm.[citation needed]

Germ plasm in fruit fly

Germ plasm has been studied in detail in Drosophila. The posterior pole of the embryo contains necessary materials for the fertility of the fly. This cytoplasm, pole plasm, contains specialized materials called polar granules and the pole cells are the precursors to primordial germ cells.[citation needed]

Pole plasm is organized by and contains the proteins and mRNA of the posterior group genes (such as oskar, nanos gene, Tudor, vasa, and Valois). These genes play a role in germ line development to localize nanos mRNA to the posterior and localize germ cell determinants. Drosophila progeny with mutations in these genes fail to produce pole cells and are thus sterile, giving these mutations the name 'grandchildless'. The genes oskar, nanos and germ cell-less (gcl) have important roles. Oskar is sufficient to recruit the other genes to form functional germ plasm. Nanos is required to prevent mitosis and somatic differentiation and for the pole cells to migrate to function as PGCs (see next section). Gcl is necessary (but not sufficient) for pole cell formation. In addition to these genes, Pgc polar granule component blocks phosphorylation and consequently activation of RNA polymerase II and shuts down transcription.[citation needed]

Germ plasm in amphibians

Similar germ plasm has been identified in Amphibians in the polar cytoplasm at the vegetal pole. This cytoplasm moves to the bottom of the blastocoel and eventually ends up as its own subset of endodermal cells. While specified to produce germ cells, the germ plasm does not irreversibly commit these cells to produce gametes and no other cell type.[1][2]

Migration of primordial germ cells

Fruit flies

The first phase of migration in Drosophila occurs when the pole cells move passively and infold into the midgut invagination. Active migration occurs through repellents and attractants. The expression of wunen in the endoderm repels the PGCs out. The expression of columbus and hedgehog attracts the PGCs to the mesodermal precursors of the gonad. Nanos is required during migration. Regardless of PGC injection site, PGCs are able to correctly migrate to their target sites.[citation needed]

Zebrafish

In zebrafish, the PGCs express two CXCR4 transmembrane receptor proteins. The signaling system involving this protein and its ligand, Sdf1, is necessary and sufficient to direct PGC migration in fish.

Frogs

In frogs, the PGCs migrate along the mesentery to the gonadal mesoderm facilitated by orientated extracellular matrix with fibronectin. There is also evidence for the CXCR4/Sdf1 system in frogs.[citation needed]

Birds

In birds, the PGCs arise from the epiblast and migrate to anteriorly of the primitive streak to the germinal crest. From there, they use blood vessels to find their way to the gonad. The CXCR4/Sdf1 system is also used, though may not be the only method necessary.[3]

Mammals

In the mouse, primordial germ cells (PGCs) arise in the posterior primitive streak of the embryo[4] and start to migrate around 6.25 days after conception. PGCs start to migrate to the embryonic endoderm and then to the hindgut and finally towards the future genital ridges where the somatic gonadal precursors reside.[4][5] This migration requires a series of attractant and repellent cues as well as a number of adhesion molecules such as E-cadherin and β1-Integrin to guide the migration of PGCs.[4] Around 10 days post conception; the PGCs occupy the genital ridge[5] where they begin to lose their motility and polarized shape.[4]

Germline development in mammals

Mammalian PGCs are specified by signalling between cells (induction), rather than by the segregation of germ plasm as the embryo divides.[6] In mice, PGCs originate from the proximal epiblast, close to the extra-embryonic ectoderm (ExE), of the post-implantation embryo as early as embryonic day 6.5.[7] By E7.5 a founding population of approximately 40 PGCs are generated in this region of the epiblast in the developing mouse embryo.[8][9][10] The epiblast, however, also give rise to somatic cell lineages that make up the embryo proper; including the endoderm, ectoderm and mesoderm.[11][12][13] The specification of primordial germ cells in mammals is mainly attributed to the downstream functions of two signaling pathways; the BMP signaling pathway and the canonical WNT/β-catenin pathway.[7]

Bone morphogenetic protein 4 (BMP4) is released by the extra-embryonic ectoderm (ExE) at embryonic day 5.5 to 5.75 directly adjacent to the epiblast[6] and causes the region of the epiblast nearest to the ExE to express Blimp1 and Prdm14 in a dose-dependent manner.[14] This is evident as the number of PGCs forming in the epiblast decreases in proportion to the loss of BMP4 alleles.[15] BMP4 acts through its downstream intercellular transcription factors SMAD1 and SMAD5.[15][16][17][18][19] During approximately the same time, WNT3 starts to be expressed in the posterior visceral endoderm of the epiblast.[20][21] WNT3 signalling has been shown to be essential in order for the epiblast to acquire responsiveness to the BMP4 signal from the ExE.[22] WNT3 mutants fail to establish a primordial germ cell population, but this can be restored with exogenous WNT activity.[23] The WNT3/β-catenin signalling pathway is essential for the expression of the transcription factor T (Brachyury), a transcription factor that was previously characterized somatic and mesoderm specific genes.[24][25] T was recently found to be both necessary and sufficient to induce the expression of the known PGC specification genes Blimp1 and Prdm14.[23] The induction of Transcription Factor T was seen 12 hours after BMP/WNT signaling, as opposed to the 24 to 36 hours it took for Blimp1 and Prdm14 genes to be expressed. Transcription factor T acts upstream of BLIMP1 and Prdm14 in PGC specification by binding to the genes respective enhancer elements.[23] It is important to note that while T can activate the expression of Blimp1 and Prdm14 in the absence of both BMP4 and WNT3, pre-exposure of PGC progenitors to WNTs (without BMP4) prevents T from activating these genes.[23] Details on how BMP4 prevents T from inducing mesodermal genes, and only activate PGC specification genes, remain unclear.

Expression of Blimp1 is the earliest known marker of PGC specification.[26] A mutation in the Blimp1 gene results in the formation of PGC-like cells at embryonic day 8.5 that closely resemble their neighbouring somatic cells.[27] A central role of Blimp 1 is the induction of Tcfap2c, a helix-span helix transcription factor.[28] Tcfap2c mutants exhibited an early loss of primordial germ cells.[29][30] Tcfap2c is thought to repress somatic gene expression, including the mesodermal marker Hoxb1.[30] So, Blimp1, Tcfap2c and Prdm14 together are able to activate and repress the transcription of all the necessary genes to regulate PGC specification.[14] Mutation of Prdm14 results in the formation of PGCs that are lost by embryonic day 11.5.[31] The loss of PGCs in the Prdm14 mutant is due to failure in global erasure of histone 3 methylation patterns.[32] Blimp1 and Prdm14 also elicit another epigenetic event that causes global DNA demethylation.[33]

Other notable genes positively regulated by Blimp1 and Prdm14 are: Sox2, Nanos3, Nanog, Stella and Fragilis.[14] At the same time, Blimp1 and Prdm14 also repress the transcription of programs that drive somatic differentiation by inhibiting transcription of the Hox family genes.[14] In this way, Blimp1 and Prdm14 drive PGC specification by promoting germ line development and potential pluripotency transcriptional programs while also keeping the cells from taking on a somatic fate.[14]

Generation of mammalian PGCs in vitro

With the vast knowledge about in-vivo PGC specification collected over the last few decades, several attempts to generate in-vitro PGCs from post-implantation epiblast were made. Various groups were able to successfully generate PGC-like cells, cultured in the presence of BMP4 and various cytokines.[15] The efficiency of this process was later enhanced by the addition of stem cell factor (SCF), epidermal growth factor (EGF), leukaemia inhibitory factor (LIF) and BMP8B.[34] PGC-like cells generated using this method can be transplanted into a gonad, where the differentiate, and are able to give viable gametes and offspring in vivo.[34] PGC-like cells can also be generated from naïve embryonic stem cells (ESCs) that are cultured for two days in the presence of FGF and Activin-A to adopt an epiblast-like state. These cells are then cultured with BMP4, BMP8B, EGF, LIF and SCF and various cytokines for four more days.[35] These in-vitro generated PGCs can also develop into viable gametes and offspring.[35]

Differentiation of primordial germ cells

Prior to their arrival at the gonads, PGCs express pluripotency factors, generate pluripotent cell lines in cell culture (known as EG cells,[36][37]) and can produce multi-lineage tumors, known as teratomas.[38] Similar findings in other vertebrates indicate that PGCs are not yet irreversibly committed to produce gametes, and no other cell type.[1][39][40] On arrival at the gonads, human and mouse PGCs activate widely conserved germ cell-specific factors, and subsequently down-regulate the expression of pluripotency factors.[41] This transition results in the determination of germ cells, a form of cell commitment that is no longer reversible.[42]

Prior to their occupation of the genital ridge, there is no known difference between XX and XY PGCs.[4] However, once migration is complete and germ cell determination has occurred, these germline cells begin to differentiate according to the gonadal niche.

Early male differentiation

Male PGCs become known as gonocytes once they cease migration and undergo mitosis.[43] The term gonocyte is generally used to describe all stages post PGC until the gonocytes differentiate into spermatogonia.[43] Anatomically, gonocytes can be identified as large, euchromatic cells that often have two nucleoli in the nucleus.[43]

In the male genital ridge, transient Sry expression causes supporting cells to differentiate into Sertoli cells which then act as the organizing center for testis differentiation. Point mutations or deletions in the human or mouse Sry coding region can lead to female development in XY individuals.[44] Sertoli cells also act to prevent gonocytes from differentiating prematurely.[45] They produce the enzyme CYP26B1 to counteract surrounding retinoic acid. Retinoic acid acts as a signal to the gonocytes to enter meiosis.[45] The gonocyte and Sertoli cells have been shown to form gap and desmosomelike junctions as well as adherins junctions composed of cadherins and connexins.[43] To differentiate into spermatogonia, the gonocytes must lose their junctions to Sertoli cells and become migratory once again.[43] They migrate to the basement membrane of the seminiferous cord[43] and differentiate.

Late differentiation

In the gonads, the germ cells undergo either spermatogenesis or oogenesis depending on whether the sex is male or female respectively.[citation needed]

Spermatogenesis

Main page: Biology:Spermatogenesis

Mitotic germ stem cells, spermatogonia, divide by mitosis to produce spermatocytes committed to meiosis. The spermatocytes divide by meiosis to form spermatids. The post-meiotic spermatids differentiate through spermiogenesis to become mature and functional spermatozoa.[citation needed] Spermatogenic cells at different stages of development in the mouse have a frequency of mutation that is 5 to 10-fold lower than the mutation frequency in somatic cells.[46]

In Drosophila, the ability of premeiotic male germ line cells to repair double-strand breaks declines dramatically with age.[47] In mouse, spermatogenesis declines with advancing paternal age likely due to an increased frequency of meiotic errors.[48]

Oogenesis

Main page: Biology:Oogenesis

Mitotic germ stem cells, oogonia, divide by mitosis to produce primary oocytes committed to meiosis. Unlike sperm production, oocyte production is not continuous. These primary oocytes begin meiosis but pause in diplotene of meiosis I while in the embryo. All of the oogonia and many primary oocytes die before birth. After puberty in primates, small groups of oocytes and follicles prepare for ovulation by advancing to metaphase II. Only after fertilization is meiosis completed. Meiosis is asymmetric producing polar bodies and oocytes with large amounts of material for embryonic development.[citation needed] The mutation frequency of female mouse germ line cells, like male germ line cells, is also lower than that of somatic cells.[49] Low germ line mutation frequency appears to be due, in part, to elevated levels of DNA repair enzymes that remove potentially mutagenic DNA damages. Enhanced genetic integrity may be a fundamental characteristic of germ line development.[49]

See also

References

  1. ↑ 1.0 1.1 "Germ plasm and germ cell determination in Xenopus laevis as studied by cell transplantation analysis". Cold Spring Harbor Symposia on Quantitative Biology 50: 37–43. 1985-01-01. doi:10.1101/SQB.1985.050.01.007. PMID 3868485. 
  2. ↑ "Specifying and protecting germ cell fate". Nature Reviews. Molecular Cell Biology 16 (7): 406–16. July 2015. doi:10.1038/nrm4009. PMID 26122616. 
  3. ↑ Lee, JH; Park, JW; Kim, SW; Park, J; Park, TS (15 December 2017). "C-X-C chemokine receptor type 4 (CXCR4) is a key receptor for chicken primordial germ cell migration.". The Journal of Reproduction and Development 63 (6): 555–562. doi:10.1262/jrd.2017-067. PMID 28867677. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Mechanisms guiding primordial germ cell migration: strategies from different organisms". Nature Reviews. Molecular Cell Biology 11 (1): 37–49. January 2010. doi:10.1038/nrm2815. PMID 20027186. 
  5. ↑ 5.0 5.1 "Building the mammalian testis: origins, differentiation, and assembly of the component cell populations". Genes & Development 27 (22): 2409–26. November 2013. doi:10.1101/gad.228080.113. PMID 24240231. 
  6. ↑ 6.0 6.1 "The molecular machinery of germ line specification". Molecular Reproduction and Development 77 (1): 3–18. January 2010. doi:10.1002/mrd.21091. PMID 19790240. 
  7. ↑ 7.0 7.1 "How to make a primordial germ cell". Electroencephalography and Clinical Neurophysiology 66 (6): 529–538. Jan 21, 2014. doi:10.1016/0013-4694(87)90100-3. PMID 2438119. 
  8. ↑ "The identification, origin, and migration of the primordial germ cells in the mouse embryo". The Anatomical Record 118 (2): 135–46. February 1954. doi:10.1002/ar.1091180202. PMID 13138919. 
  9. ↑ "Primordial germ cells in the mouse embryo during gastrulation". Development 110 (2): 521–8. October 1990. doi:10.1242/dev.110.2.521. PMID 2133553. http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=2133553. 
  10. ↑ "Clonal Analysis of the Origin of Primordial Germ Cells in the Mouse". Ciba Foundation Symposium 182 ‐ Germline Development. Novartis Foundation Symposia. 182. 1994. 68–84; discussion 84–91. doi:10.1002/9780470514573.ch5. ISBN 978-0-470-51457-3. 
  11. ↑ "Lineage specification in the early mouse embryo". Experimental Cell Research 321 (1): 32–9. February 2014. doi:10.1016/j.yexcr.2013.12.004. PMID 24333597. 
  12. ↑ "Anatomy of a blastocyst: cell behaviors driving cell fate choice and morphogenesis in the early mouse embryo". Genesis 51 (4): 219–33. April 2013. doi:10.1002/dvg.22368. PMID 23349011. 
  13. ↑ Gilbert, Scott F. (2013). Developmental biology (10th ed.). Sunderland: Sinauer Associates. ISBN 978-1-60535-173-5. [page needed]
  14. ↑ 14.0 14.1 14.2 14.3 14.4 "Primordial germ cells in mice". Cold Spring Harbor Perspectives in Biology 4 (11): a008375. November 2012. doi:10.1101/cshperspect.a008375. PMID 23125014. 
  15. ↑ 15.0 15.1 15.2 "Bmp4 is required for the generation of primordial germ cells in the mouse embryo". Genes & Development 13 (4): 424–36. February 1999. doi:10.1101/gad.13.4.424. PMID 10049358. 
  16. ↑ "SMAD1 signaling is critical for initial commitment of germ cell lineage from mouse epiblast". Mechanisms of Development 118 (1–2): 99–109. October 2002. doi:10.1016/S0925-4773(02)00237-X. PMID 12351174. 
  17. ↑ "Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos". Journal of Embryology and Experimental Morphology 64: 133–47. August 1981. PMID 7310300. http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=7310300. 
  18. ↑ "Cooperation of endoderm-derived BMP2 and extraembryonic ectoderm-derived BMP4 in primordial germ cell generation in the mouse". Developmental Biology 232 (2): 484–92. April 2001. doi:10.1006/dbio.2001.0173. PMID 11401407. 
  19. ↑ "Requirement of Bmp8b for the generation of primordial germ cells in the mouse". Molecular Endocrinology 14 (7): 1053–63. July 2000. doi:10.1210/mend.14.7.0479. PMID 10894154. 
  20. ↑ "Requirement for Wnt3 in vertebrate axis formation". Nature Genetics 22 (4): 361–5. August 1999. doi:10.1038/11932. PMID 10431240. 
  21. ↑ "Primitive streak formation in mice is preceded by localized activation of Brachyury and Wnt3". Developmental Biology 288 (2): 363–71. December 2005. doi:10.1016/j.ydbio.2005.09.012. PMID 16289026. 
  22. ↑ "Dullard/Ctdnep1 modulates WNT signalling activity for the formation of primordial germ cells in the mouse embryo". PLOS ONE 8 (3): e57428. 2013. doi:10.1371/journal.pone.0057428. PMID 23469192. Bibcode: 2013PLoSO...857428T. 
  23. ↑ 23.0 23.1 23.2 23.3 "A mesodermal factor, T, specifies mouse germ cell fate by directly activating germline determinants". Developmental Cell 27 (5): 516–29. December 2013. doi:10.1016/j.devcel.2013.11.001. PMID 24331926. 
  24. ↑ "Cloning of the T gene required in mesoderm formation in the mouse". Nature 343 (6259): 617–22. February 1990. doi:10.1038/343617a0. PMID 2154694. Bibcode: 1990Natur.343..617H. 
  25. ↑ "T-box genes in vertebrate development". Annual Review of Genetics 39: 219–39. 2005. doi:10.1146/annurev.genet.39.073003.105925. PMID 16285859. 
  26. ↑ "Germ cells are forever". Cell 132 (4): 559–62. February 2008. doi:10.1016/j.cell.2008.02.003. PMID 18295574. 
  27. ↑ "Blimp1 is a critical determinant of the germ cell lineage in mice". Nature 436 (7048): 207–13. July 2005. doi:10.1038/nature03813. PMID 15937476. Bibcode: 2005Natur.436..207O. 
  28. ↑ "Transcription factor gene AP-2 gamma essential for early murine development". Molecular and Cellular Biology 22 (9): 3149–56. May 2002. doi:10.1128/mcb.22.9.3149-3156.2002. PMID 11940672. 
  29. ↑ "A tripartite transcription factor network regulates primordial germ cell specification in mice". Nature Cell Biology 15 (8): 905–15. August 2013. doi:10.1038/ncb2798. PMID 23851488. 
  30. ↑ 30.0 30.1 "Critical function of AP-2 gamma/TCFAP2C in mouse embryonic germ cell maintenance". Biology of Reproduction 82 (1): 214–23. January 2010. doi:10.1095/biolreprod.109.078717. PMID 19776388. 
  31. ↑ "Chromatin dynamics during epigenetic reprogramming in the mouse germ line". Nature 452 (7189): 877–81. April 2008. doi:10.1038/nature06714. PMID 18354397. Bibcode: 2008Natur.452..877H. 
  32. ↑ "Genome-wide reprogramming in the mouse germ line entails the base excision repair pathway". Science 329 (5987): 78–82. July 2010. doi:10.1126/science.1187945. PMID 20595612. Bibcode: 2010Sci...329...78H. 
  33. ↑ "Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine". Science 339 (6118): 448–52. January 2013. doi:10.1126/science.1229277. PMID 23223451. Bibcode: 2013Sci...339..448H. 
  34. ↑ 34.0 34.1 "A signaling principle for the specification of the germ cell lineage in mice". Cell 137 (3): 571–84. May 2009. doi:10.1016/j.cell.2009.03.014. PMID 19410550. 
  35. ↑ 35.0 35.1 "Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells". Cell 146 (4): 519–32. August 2011. doi:10.1016/j.cell.2011.06.052. PMID 21820164. 
  36. ↑ "Long-term proliferation of mouse primordial germ cells in culture". Nature 359 (6395): 550–1. October 1992. doi:10.1038/359550a0. PMID 1383830. Bibcode: 1992Natur.359..550R. 
  37. ↑ "Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture" (in en). Cell 70 (5): 841–7. September 1992. doi:10.1016/0092-8674(92)90317-6. PMID 1381289. https://www.cell.com/cell/abstract/0092-8674(92)90317-6. 
  38. ↑ "Spontaneous Testicular Teratomas in an Inbred Strain of Mice". Proceedings of the National Academy of Sciences of the United States of America 40 (11): 1080–7. November 1954. doi:10.1073/pnas.40.11.1080. PMID 16578442. Bibcode: 1954PNAS...40.1080S. 
  39. ↑ "The Vertebrate Protein Dead End Maintains Primordial Germ Cell Fate by Inhibiting Somatic Differentiation". Developmental Cell 43 (6): 704–715.e5. December 2017. doi:10.1016/j.devcel.2017.11.019. PMID 29257950. 
  40. ↑ "Stochastic specification of primordial germ cells from mesoderm precursors in axolotl embryos". Development 141 (12): 2429–40. June 2014. doi:10.1242/dev.105346. PMID 24917499. 
  41. ↑ "Mammalian germ cells are determined after PGC colonization of the nascent gonad". Proceedings of the National Academy of Sciences of the United States of America 116 (51): 25677–25687. November 2019. doi:10.1073/pnas.1910733116. PMID 31754036. Bibcode: 2019PNAS..11625677N. 
  42. ↑ Slack, J. M. W. (May 1991) (in en). From Egg to Embryo: Regional Specification in Early Development. Cambridge Core. doi:10.1017/cbo9780511525322. ISBN 9780521401081. https://www.cambridge.org/core/books/from-egg-to-embryo/8F2B8E10213857CE205DD9918B58AEF1. Retrieved 2019-11-27. 
  43. ↑ 43.0 43.1 43.2 43.3 43.4 43.5 "Gonocytes, from the fifties to the present: is there a reason to change the name?". Biology of Reproduction 89 (2): 46. August 2013. doi:10.1095/biolreprod.113.110544. PMID 23843237. 
  44. ↑ "Genetic control of testis development". Sexual Development 7 (1–3): 21–32. 2013. doi:10.1159/000342221. PMID 22964823. 
  45. ↑ 45.0 45.1 "Paracrine mechanisms involved in the control of early stages of Mammalian spermatogenesis". Frontiers in Endocrinology 4: 181. November 2013. doi:10.3389/fendo.2013.00181. PMID 24324457. 
  46. ↑ "Mutation frequency declines during spermatogenesis in young mice but increases in old mice". Proceedings of the National Academy of Sciences of the United States of America 95 (17): 10015–9. August 1998. doi:10.1073/pnas.95.17.10015. PMID 9707592. Bibcode: 1998PNAS...9510015W. 
  47. ↑ "Aging impairs double-strand break repair by homologous recombination in Drosophila germ cells". Aging Cell 16 (2): 320–328. April 2017. doi:10.1111/acel.12556. PMID 28000382. 
  48. ↑ "Evidence for paternal age-related alterations in meiotic chromosome dynamics in the mouse". Genetics 196 (2): 385–96. February 2014. doi:10.1534/genetics.113.158782. PMID 24318536. 
  49. ↑ 49.0 49.1 "Enhanced genetic integrity in mouse germ cells". Biology of Reproduction 88 (1): 6. January 2013. doi:10.1095/biolreprod.112.103481. PMID 23153565. 



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