Biology:Germ line development

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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 germ line 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. These cells eventually become PGCs. The presence of homologs of nanos and vasa also implicate this germ plasm as germ-determining.[citation needed]

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 ridge. From there, they use blood vessels to find their way to the gonad. It is possible that the CXCR4/Sdf1 system is used.[citation needed]

Mammals

In the mouse, primordial germ cells (PGCs) arise in the posterior primitive streak of the embryo[1] 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.[1][2] 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.[1] Around 10 days post conception; the PGCs occupy the genital ridge[2] where they begin to lose their motility and polarized shape.[1]

Germ line development in mammals

Mammalian PGCs are specified by signalling between cells (induction), rather than by the segregation of germ plasm as the embryo divides.[3] 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.[4] By E7.5 a founding population of approximately 40 PGCs are generated in this region of the epiblast in the developing mouse embryo.[5][6][7] The epiblast, however, also give rise to somatic cell lineages that make up the embryo proper; including the endoderm, ectoderm and mesoderm.[8][9][10] 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.[11]

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[3] and causes the region of the epiblast nearest to the ExE to express Blimp1 and Prdm4 in a dose-dependent manner.[12] This is evident as the number of PGCs forming in the epiblast decreases in proportion to the loss of BMP4 alleles.[13] BMP4 acts through its downstream intercellular transcription factors SMAD1 and SMAD5.[13][14][15][16][17] During approximately the same time, WNT3 starts to be expressed in the posterior visceral endoderm of the epiblast.[18][19] WNT3 signalling has been shown to be essential in order for the epiblast to acquire responsiveness to the BMP4 signal from the ExE.[20] WNT3 mutants fail to establish a primordial germ cell population, but this can be restored with exogenous WNT activity.[21] The WNT3/β-catenin signalling pathway is essential for the expression of the transcription factor T (Brachyury), a transcription factor that is was previously characterized somatic and mesoderm specific genes.[22][23] T was recently found to be both necessary and sufficient to induce the expression of the known PGC specification genes Blimp1 and Prdm4.[21] 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 Prdm4 genes to be expressed. Transcription factor T acts upstream of BLIMP1 and PRDM4 in PGC specification by binding to the genes respective enhancer elements.[21] It is important to note that while T can activate the expression of Blimp1 and Prdm4 in the absence of both BMP4 and WNT3, pre-exposure of PGC progenitors to WNTs (without BMP4) prevents T from activating these genes.[21] 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.[24] 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.[25] A central role of Blimp 1 is the induction of Tcfap2c, a helix-span helix transcription factor.[26] Tcfap2c mutants exhibited an early loss of primordial germ cells.[27][28] Tcfap2c is thought to repress somatic gene expression, including the mesodermal marker Hoxb1.[28] So, Blimp1, Tcfap2c and Prdm4 together are able to activate and repress the transcription of all the necessary genes to regulate PGC specification.[12] Mutation of Prdm4 results in the formation of PGCs that are lost by embryonic day 11.5.[29] The loss of PGCs in the Prdm4 mutant is due to failure in global erasure of histone 3 methylation patterns.[30] Blimp1 and Prdm4 also elicit another epigenetic event that causes global DNA demethylation.[31]

Other notable genes positively regulated by Blimp1 and Prdm4 are: Sox2, Nanos3, Nanog, Stella and Fragilis.[12] At the same time, Blimp1 and Prdm4 also repress the transcription of programs that drive somatic differentiation by inhibiting transcription of the Hox family genes.[12] In this way, Blimp1 and Prdm4 drive PGC specification by promoting germ line development and potential pluripotency transcriptional programs while also keeping the cells from taking on a somatic fate.[12]

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 PGCs, cultured in the presences of BMP4 and various cytokines.[13] 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.[32] PGCs generated using this method can be transplanted to give viable gametes and offspring in vivo.[32] PGCs 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.[33] These in-vitro generated PGCs can also develop into viable gametes and offspring.[33]

Differentiation of primordial germ cells

Prior to their occupation of the genital ridge, there is no known difference between XX and XY PGCs.[1] However, once migration is complete, male and female PGCs begin to differentiate differently.

Early male differentiation

Male PGCs become known as gonocytes once they cease migration and undergo mitosis.[34] The term gonocyte is generally used to describe all stages post PGC until the gonocytes differentiate into spermatogonia.[34] Anatomically, gonocytes can be identified as large, euchromatic cells that often have two nucleoli in the nucleus.[34]

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.[35] Sertoli cells also act to prevent gonocytes from differentiating prematurely.[36] They produce the enzyme CYP26B1 to counteract surrounding retinoic acid. Retinoic acid acts as a signal to the gonocytes to enter meiosis.[36] The gonocyte and Sertoli cells have been shown to form gap and desmosomelike junctions as well as adherins junctions composed of cadherins and connexins.[34] To differentiate into spermatogonia, the gonocytes must lose their junctions to Sertoli cells and become migratory once again.[34] They migrate to the basement membrane of the seminiferous cord[34] 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.[37]

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.[38] 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.[38]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "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. 
  2. ↑ 2.0 2.1 "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. 
  3. ↑ 3.0 3.1 "The molecular machinery of germ line specification". Molecular Reproduction and Development 77 (1): 3–18. January 2010. doi:10.1002/mrd.21091. PMID 19790240. 
  4. ↑ "Human short-latency auditory responses obtained by cross-correlation". Electroencephalography and Clinical Neurophysiology 66 (6): 529–38. June 1987. doi:10.1016/0013-4694(87)90100-3. PMID 2438119. 
  5. ↑ Chiquoine AD (February 1954). "The identification, origin, and migration of the primordial germ cells in the mouse embryo". The Anatomical Record 118 (2): 135–46. doi:10.1002/ar.1091180202. PMID 13138919. 
  6. ↑ "Primordial germ cells in the mouse embryo during gastrulation". Development 110 (2): 521–8. October 1990. PMID 2133553. http://dev.biologists.org/cgi/pmidlookup?view=long&pmid=2133553. 
  7. ↑ "Clonal analysis of the origin of primordial germ cells in the mouse". Ciba Foundation Symposium. Novartis Foundation Symposia 182: 68–84; discussion 84–91. 1994. doi:10.1002/9780470514573.ch5. ISBN 978-0-470-51457-3. PMID 7835158. 
  8. ↑ Lanner F (February 2014). "Lineage specification in the early mouse embryo". Experimental Cell Research 321 (1): 32–9. doi:10.1016/j.yexcr.2013.12.004. PMID 24333597. 
  9. ↑ "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. 
  10. ↑ Gilbert, Scott F. (2013). Developmental biology (10th ed.). Sunderland: Sinauer Associates. ISBN 978-1-60535-173-5. [page needed]
  11. ↑ "How to make a primordial germ cell". Development 141 (2): 245–52. January 2014. doi:10.1242/dev.098269. PMID 24381195. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 "Primordial germ cells in mice". Cold Spring Harbor Perspectives in Biology 4 (11): a008375. November 2012. doi:10.1101/cshperspect.a008375. PMID 23125014. 
  13. ↑ 13.0 13.1 13.2 "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. PMC 316469. http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=10049358. 
  14. ↑ "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. 
  15. ↑ "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. 
  16. ↑ "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. 
  17. ↑ "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. 
  18. ↑ "Requirement for Wnt3 in vertebrate axis formation". Nature Genetics 22 (4): 361–5. August 1999. doi:10.1038/11932. PMID 10431240. 
  19. ↑ "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. 
  20. ↑ Tanaka, Satomi S.; Nakane, Akihiro; Yamaguchi, Yasuka L.; Terabayashi, Takeshi; Abe, Takaya; Nakao, Kazuki; Asashima, Makoto; Steiner, Kirsten A. et al. (2013). "Dullard/Ctdnep1 Modulates WNT Signalling Activity for the Formation of Primordial Germ Cells in the Mouse Embryo". PLoS ONE 8 (3): 57428. doi:10.1371/journal.pone.0057428. PMID 23469192. Bibcode: 2013PLoSO...857428T. 
  21. ↑ 21.0 21.1 21.2 21.3 "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. 
  22. ↑ Herrmann, Bernhard G.; Labeit, Siegfried; Poustka, Annemarie; King, Thomas R.; Lehrach, Hans (1990). "Cloning of the T gene required in mesoderm formation in the mouse". Nature 343 (6259): 617–22. doi:10.1038/343617a0. PMID 2154694. Bibcode: 1990Natur.343..617H. 
  23. ↑ "T-box genes in vertebrate development". Annual Review of Genetics 39: 219–39. 2005. doi:10.1146/annurev.genet.39.073003.105925. PMID 16285859. 
  24. ↑ "Germ cells are forever". Cell 132 (4): 559–62. February 2008. doi:10.1016/j.cell.2008.02.003. PMID 18295574. 
  25. ↑ Ohinata, Yasuhide; Payer, Bernhard; O'Carroll, Dónal; Ancelin, Katia; Ono, Yukiko; Sano, Mitsue; Barton, Sheila C.; Obukhanych, Tetyana et al. (2005). "Blimp1 is a critical determinant of the germ cell lineage in mice". Nature 436 (7048): 207–13. doi:10.1038/nature03813. PMID 15937476. Bibcode: 2005Natur.436..207O. 
  26. ↑ "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. PMC 133770. http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=11940672. 
  27. ↑ "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. 
  28. ↑ 28.0 28.1 "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. 
  29. ↑ Hajkova, Petra; Ancelin, Katia; Waldmann, Tanja; Lacoste, Nicolas; Lange, Ulrike C.; Cesari, Francesca; Lee, Caroline; Almouzni, Genevieve et al. (2008). "Chromatin dynamics during epigenetic reprogramming in the mouse germ line". Nature 452 (7189): 877–81. doi:10.1038/nature06714. PMID 18354397. Bibcode: 2008Natur.452..877H. 
  30. ↑ Hajkova, Petra; Jeffries, Sean J.; Lee, Caroline; Miller, Nigel; Jackson, Stephen P.; Surani, M. Azim (2010). "Genome-Wide Reprogramming in the Mouse Germ Line Entails the Base Excision Repair Pathway". Science 329 (5987): 78–82. doi:10.1126/science.1187945. PMID 20595612. Bibcode: 2010Sci...329...78H. 
  31. ↑ Hackett, Jamie A.; Sengupta, Roopsha; Zylicz, Jan J.; Murakami, Kazuhiro; Lee, Caroline; Down, Thomas A.; Surani, M. Azim (2013). "Germline DNA Demethylation Dynamics and Imprint Erasure Through 5-Hydroxymethylcytosine". Science 339 (6118): 448–52. doi:10.1126/science.1229277. PMID 23223451. Bibcode: 2013Sci...339..448H. 
  32. ↑ 32.0 32.1 "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. 
  33. ↑ 33.0 33.1 "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. 
  34. ↑ 34.0 34.1 34.2 34.3 34.4 34.5 Culty M (August 2013). "Gonocytes, from the fifties to the present: is there a reason to change the name?". Biology of Reproduction 89 (2): 46. doi:10.1095/biolreprod.113.110544. PMID 23843237. 
  35. ↑ "Genetic control of testis development". Sexual Development 7 (1–3): 21–32. 2013. doi:10.1159/000342221. PMID 22964823. 
  36. ↑ 36.0 36.1 "Paracrine Mechanisms Involved in the Control of Early Stages of Mammalian Spermatogenesis". Frontiers in Endocrinology 4: 181. 2013. doi:10.3389/fendo.2013.00181. PMID 24324457. 
  37. ↑ "Mutation frequency declines during spermatogenesis in young mice but increases in old mice". Proc. Natl. Acad. Sci. U.S.A. 95 (17): 10015–9. 1998. doi:10.1073/pnas.95.17.10015. PMID 9707592. Bibcode: 1998PNAS...9510015W. 
  38. ↑ 38.0 38.1 "Enhanced genetic integrity in mouse germ cells". Biol. Reprod. 88 (1): 6. 2013. doi:10.1095/biolreprod.112.103481. PMID 23153565. 




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