Editing Germ cell

{{For|the colloquial term for a disease causing agent, or other various meanings|Germ (disambiguation)}}{{Short description|Gamete-producing cell}}
{{More citations needed|date=December 2023}}
{{Sex (biology) sidebar}}
A '''germ cell''' is any cell that gives rise to the [[gamete]]s of an organism that [[sexual reproduction|reproduces sexually]]. In many animals, the germ cells originate in the [[primitive streak]] and migrate via the [[Gut (zoology)|gut]] of an [[embryo]] to the developing [[gonads]]. There, they undergo [[meiosis]], followed by [[cellular differentiation]] into mature gametes, either [[egg cell|eggs]] or [[sperm]]. Unlike animals, [[plant reproductive morphology|plant]]s do not have germ cells designated in early development. Instead, germ cells can arise from [[somatic cell]]s in the adult, such as the floral [[meristem]] of [[flowering plant]]s.<ref>{{cite book|title=Molecular biology of the cell|url=https://archive.org/details/molecularbiolog000wils|url-access=registration| vauthors = Alberts B, Johnson A, Lewis J, Raff Mm Roberts K, Walter P | publisher = New York, Garland Science, 1463 p|year=2002|isbn=9780815335771}}</ref><ref>{{cite book|title=Developmental biology| vauthors = Twyman RM| publisher = Oxford, Bios Scientific Publishers, 451p|year=2001}}</ref><ref>{{cite journal | vauthors = Cinalli RM, Rangan P, Lehmann R | title = Germ cells are forever | journal = Cell | volume = 132 | issue = 4 | pages = 559–562 | date = February 2008 | pmid = 18295574 | doi = 10.1016/j.cell.2008.02.003 | s2cid = 15768958 | doi-access = free }}</ref>

==Introduction==
Multicellular [[eukaryote]]s are made of two fundamental cell types: '''germ''' and '''somatic''' cells. Germ cells produce gametes and are the only cells that can undergo [[meiosis]] as well as [[mitosis]]. [[Somatic cell]]s are all the other cells that form the building blocks of the body and they only divide by mitosis. The lineage of germ cells is called the [[germline]]. Germ cell specification begins during [[cleavage (embryo)|cleavage]] in many animals or in the [[epiblast]] during [[gastrulation]] in [[bird]]s and [[mammal]]s. After transport, involving passive movements and active migration, germ cells arrive at the developing gonads. In humans, sexual differentiation starts approximately 6 weeks after conception. The end-products of the germ cell cycle are the egg or sperm.<ref>{{cite journal | vauthors = Kunwar PS, Lehmann R | title = Developmental biology: Germ-cell attraction | journal = Nature | volume = 421 | issue = 6920 | pages = 226–227 | date = January 2003 | pmid = 12529629 | doi = 10.1038/421226a | s2cid = 29737428 | doi-access = free | bibcode = 2003Natur.421..226K }}</ref>

Under special conditions ''[[in vitro]]'' germ cells can acquire properties similar to those of [[embryonic stem cells]] (ESCs). The underlying mechanism of that change is still unknown. These changed cells are then called embryonic germ cells. Both cell types are [[pluripotent]] in vitro, but only ESCs have proven pluripotency in vivo. Recent studies have demonstrated that it is possible to give rise to primordial germ cells from ESCs.<ref>{{cite journal | vauthors = Turnpenny L, Spalluto CM, Perrett RM, O'Shea M, Hanley KP, Cameron IT, Wilson DI, Hanley NA | display-authors = 6 | title = Evaluating human embryonic germ cells: concord and conflict as pluripotent stem cells | journal = Stem Cells | volume = 24 | issue = 2 | pages = 212–220 | date = February 2006 | pmid = 16144875 | doi = 10.1634/stemcells.2005-0255 | s2cid = 20446427 | doi-access = free }}</ref>

==Specification==
There are two mechanisms to establish the germ cell lineage in the [[embryo]]. The first way is called preformistic and involves that the cells destined to become germ cells inherit the specific germ cell determinants present in the [[germ plasm]] (specific area of the cytoplasm) of the egg (ovum). The unfertilized egg of most animals is asymmetrical: different regions of the cytoplasm contain different amounts of [[Messenger RNA|mRNA]] and proteins.

The second way is found in mammals, where germ cells are not specified by such determinants but by signals controlled by zygotic genes. In mammals, a few cells of the early embryo are induced by signals of neighboring cells to become [[Germ line development#Germline development in mammals|primordial germ cells]]. Mammalian eggs are somewhat symmetrical and after the first divisions of the fertilized egg, the produced cells are all [[totipotent]]. This means that they can differentiate in any cell type in the body and thus germ cells. Specification of primordial germ cells in the laboratory mouse is initiated by high levels of bone morphogenetic protein (BMP) signaling, which activates expression of the transcription factors Blimp-1/[[PRDM1|Prdm1]] and Prdm14.<ref name="Saitou">{{cite journal | vauthors = Saitou M, Yamaji M | title = Primordial germ cells in mice | journal = Cold Spring Harbor Perspectives in Biology | volume = 4 | issue = 11 | pages = a008375 | date = November 2012 | pmid = 23125014 | pmc = 3536339 | doi = 10.1101/cshperspect.a008375 }}</ref>

It is speculated that induction was the ancestral mechanism, and that the preformistic, or inheritance, mechanism of germ cell establishment arose from [[convergent evolution]].<ref>{{cite journal | vauthors = Johnson AD, Alberio R | title = Primordial germ cells: the first cell lineage or the last cells standing? | journal = Development | volume = 142 | issue = 16 | pages = 2730–2739 | date = August 2015 | pmid = 26286941 | pmc = 4550962 | doi = 10.1242/dev.113993 }}</ref> There are several key differences between these two mechanisms that may provide reasoning for the evolution of germ plasm inheritance. One difference is that typically inheritance occurs almost immediately during development (around the [[blastoderm]] stage) while induction typically does not occur until gastrulation. As germ cells are quiescent and therefore not dividing, they are not susceptible to mutation.

Since the germ cell lineage is not established right away by induction, there is a higher chance for mutation to occur before the cells are specified. Mutation rate data is available that indicates a higher rate of germ line mutations in mice and humans, species which undergo induction, than in C. elegans and Drosophila melanogaster, species which undergo inheritance.<ref>{{cite journal | vauthors = Whittle CA, Extavour CG | title = Causes and evolutionary consequences of primordial germ-cell specification mode in metazoans | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 23 | pages = 5784–5791 | date = June 2017 | pmid = 28584112 | pmc = 5468662 | doi = 10.1073/pnas.1610600114 | bibcode = 2017PNAS..114.5784W | doi-access = free }}</ref> A lower mutation rate would be selected for, which is one possible reason for the convergent evolution of the germ plasm. However, more mutation rate data will need to be collected across several taxa, particularly data collected both before and after the specification of primordial germ cells before this hypothesis on the evolution of germ plasm can be backed by strong evidence.

==Migration==
{{Main|Primordial germ cell migration}}
Primordial germ cells, germ cells that still have to reach the gonads (also known as PGCs, precursor germ cells or gonocytes) divide repeatedly on their migratory route through the gut and into the developing gonads.<ref>{{Cite book | vauthors = Gilbert SF |date=2000| chapter = Germ Cell Migration | chapter-url= https://www.ncbi.nlm.nih.gov/books/NBK10045/| title = Developmental Biology | edition = 6th | location = Sunderland (MA) | publisher = Sinauer Associates |language=en}}</ref>

===Invertebrates===
In the [[model organism]] ''[[Drosophila]]'', pole cells passively move from the [[anatomical terms of location#Anterior and posterior|posterior]] end of the embryo to the posterior midgut because of the infolding of the blastoderm. Then they actively move through the gut into the [[mesoderm]]. [[Endoderm]]al cells differentiate and together with Wunen proteins they induce the migration through the gut. Wunen proteins are [[chemorepellent]]s that lead the germ cells away from the endoderm and into the mesoderm. After splitting into two populations, the germ cells continue migrating laterally and in parallel until they reach the gonads. Columbus proteins, [[chemoattractant]]s, stimulate the migration in the gonadal mesoderm.{{citation needed|date=December 2011}}

===Vertebrates===
In the aquatic frog ''[[Xenopus]]'' egg, the germ cell determinants are found in the most [[vegetal pole|vegetal]] [[blastomere]]s. These presumptive PGCs are brought to the endoderm of the [[blastocoel]] by [[gastrulation]]. They are determined as germ cells when gastrulation is completed. Migration from the hindgut along the gut and across the dorsal [[mesentery]] then takes place. The germ cells split into two populations and move to the paired gonadal ridges. Migration starts with 3-4 cells that undergo three rounds of cell division so that about 30 PGCs arrive at the gonads. On the migratory path of the PGCs, the orientation of underlying cells and their secreted molecules such as [[fibronectin]] play an important role.{{citation needed|date=December 2011}}

Mammals have a migratory path comparable to that in ''Xenopus''. Migration begins with 50 gonocytes and about 5,000 PGCs arrive at the gonads. Proliferation occurs also during migration and lasts for 3–4 weeks in humans.{{citation needed|date=December 2011}}

PGCs come from the [[epiblast]] and migrate subsequently into the mesoderm, the endoderm and the posterior of the [[yolk sac]]. Migration then takes place from the [[hindgut]] along the gut and across the dorsal mesentery to reach the gonads (4.5 weeks in human beings). [[Fibronectin]] maps here also a polarized network together with other molecules. The somatic cells on the path of germ cells provide them attractive, repulsive, and survival signals. But germ cells also send signals to each other.{{citation needed|date=December 2011}}

In [[reptile]]s and [[bird]]s, germ cells use another path. PGCs come from the epiblast and move to the [[hypoblast]] to form the germinal crescent ([[anatomical terms of location#Anterior and posterior|anterior]] extraembryonic structure). The [[gonocyte]]s then squeeze into [[blood vessel]]s and use the [[circulatory system]] for transport. They squeeze out of the vessels when they are at height of the [[gonadal ridge]]s. [[Cell adhesion]] on the [[endothelium]] of the blood vessels and molecules such as [[chemoattractant]]s are probably involved in helping PGCs migrate.{{citation needed|date=December 2011}}

====The ''Sry'' gene of the Y chromosome====
The Sex-determining Region of the Y [[chromosome]] (''[[SRY]]'') directs male development in mammals by inducing the somatic cells of the gonadal ridge to develop into a testis, rather than an ovary.<ref name="Alberts">{{cite book |chapter=Primordial Germ Cells and Sex Determination in Mammals | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK26940/|title=Molecular Biology of the Cell. | edition = 4th . | vauthors = Alberts B, Johnson A, Lewis J, etal |publisher=Garland Science|year=2002}}</ref> ''Sry'' is expressed in a small group of [[somatic cell]]s of the gonads and influences these cells to become [[Sertoli cells]] (supporting cells in testis). Sertoli cells are responsible for sexual development along a male pathway in many ways. One of these ways involves stimulation of the arriving primordial cells to differentiate into [[sperm]]. In the absence of the ''Sry'' gene, primordial germ cells differentiate into [[egg (biology)|eggs]]. Removing genital ridges before they start to develop into [[testes]] or [[ovary|ovaries]] results in the development of a female, independent of the carried [[sex chromosome]].<ref name="Alberts"/>

====Retinoic Acid  and Germ cell differentiation====
Retinoic acid (RA) is an important factor that causes differentiation of primordial germ cells.  In males, the mesonephros releases retinoic acid. RA then goes to the gonad causing an enzyme called CYP26B1 to be released by sertoli cells. CYP26B1 metabolizes RA, and because sertoli cells surround primordial germ cells (PGCs), PGCs never come into contact with RA, which results in a lack of proliferation of PGCs and no meiotic entry. This keeps spermatogenesis from starting too soon.  In females, the mesonephros releases RA, which enters the gonad. RA stimulates Stra8, a critical gatekeeper of meiosis (1), and Rec8, causing primordial germ cells to enter meiosis. This causes the development of oocytes that arrest in meiosis I.<ref name="pmid28853925">{{cite journal | vauthors = Spiller C, Koopman P, Bowles J | title = Sex Determination in the Mammalian Germline | journal = Annual Review of Genetics | volume = 51 | pages = 265–285 | date = November 2017 | pmid = 28853925 | doi = 10.1146/annurev-genet-120215-035449 }}</ref>

==Gametogenesis==
[[Gametogenesis]], the development of [[diploid]] germ cells into either [[haploid]] eggs or sperm (respectively oogenesis and spermatogenesis) is different for each [[species]] but the general stages are similar. [[Oogenesis]] and [[spermatogenesis]] have many features in common, they both involve:
* [[Meiosis]]
* Extensive [[morphology (biology)|morphological]] differentiation
* Incapacity of surviving for very long if fertilization does not occur

Despite their homologies they also have major differences:{{citation needed|date=December 2011}}
* Spermatogenesis has equivalent meiotic divisions resulting in four equivalent [[spermatid]]s while oogenic meiosis is [[asymmetrical]]: only one egg is formed together with a first and second [[polar bodies]].
* Different timing of maturation: oogenic meiosis is interrupted at one or more stages (for a long time) while spermatogenic meiosis is rapid and uninterrupted.

==Oogenesis==
After migration primordial germ cells will become oogonia in the forming gonad (ovary). The oogonia proliferate extensively by mitotic divisions, up to 5-7 million cells in humans. But then many of these oogonia die and about 50,000 remain. These cells differentiate into primary oocytes. In week 11-12 ''post coitus'' the first meiotic division begins (before birth for most mammals) and remains arrested in prophase I from a few days to many years depending on the species. It is in this period or in some cases at the beginning of sexual maturity that the primary oocytes secrete proteins to form a coat called [[zona pellucida]] and they also produce [[cortical granules]] containing enzymes and proteins needed for fertilization. Meiosis stands by because of the [[follicular granulosa cell]]s that send inhibitory signals through [[gap junction]]s and the zona pellucida. Sexual maturation is the beginning of periodic ovulation. [[Ovulation]] is the regular release of one oocyte from the ovary into the reproductive tract and is preceded by follicular growth. A few follicle cells are stimulated to grow but only one oocyte is ovulated. A primordial follicle consists of an epithelial layer of follicular granulosa cells enclosing an oocyte. The [[pituitary gland]] secrete [[follicle-stimulating hormone]]s (FSHs) that stimulate follicular growth and oocyte maturation. The [[thecal cell]]s around each follicle secrete [[estrogen]]. This hormone stimulates the production of FSH receptors on the follicular granulosa cells and has at the same time a negative feedback on FSH secretion. This results in a competition between the follicles and only the follicle with the most FSH receptors survives and is ovulated. Meiotic division I goes on in the ovulated oocyte stimulated by [[luteinizing hormone]]s (LHs) produced by the [[pituitary gland]]. FSH and LH block the gap junctions between follicle cells and the oocyte therefore inhibiting communication between them. Most follicular granulosa cells stay around the oocyte and so form the cumulus layer. Large non-mammalian oocytes accumulate [[egg yolk]], [[glycogen]], [[lipid]]s, [[ribosome]]s, and the [[mRNA]] needed for protein synthesis during early embryonic growth. These intensive RNA biosynthese are mirrored in the structure of the [[chromosome]]s, which decondense and form lateral loops giving them a lampbrush appearance (see [[Lampbrush chromosome]]). Oocyte maturation is the following phase of oocyte development. It occurs at sexual maturity when hormones stimulate the oocyte to complete meiotic division I. The meiotic division I produces 2 cells differing in size: a small polar body and a large secondary oocyte. The secondary oocyte undergoes meiotic division II and that results in the formation of a second small polar body and a large mature egg, both being [[haploid]] cells. The polar bodies degenerate.<ref>{{cite journal | vauthors = De Felici M, Scaldaferri ML, Lobascio M, Iona S, Nazzicone V, Klinger FG, Farini D | title = Experimental approaches to the study of primordial germ cell lineage and proliferation | journal = Human Reproduction Update | volume = 10 | issue = 3 | pages = 197–206 | year = 2004 | pmid = 15140867 | doi = 10.1093/humupd/dmh020 | doi-access = free }}</ref> Oocyte maturation stands by at metaphase II in most vertebrates. During ovulation, the arrested secondary oocyte leaves the ovary and matures rapidly into an egg ready for fertilization. Fertilization will cause the egg to complete meiosis II. In human females there is proliferation of the oogonia in the fetus, meiosis starts then before birth and stands by at meiotic division I up to 50 years, ovulation begins at [[puberty]].{{citation needed|date=December 2011}}

===Egg growth===

A 10 - 20 μm large somatic cell generally needs 24 hours to double its [[mass]] for mitosis. By this way it would take a very long time for that cell to reach the size of a mammalian egg with a diameter of 100 μm (some insects have eggs of about 1,000 μm or greater). Eggs have therefore special mechanisms to grow to their large size. One of these mechanisms is to have extra copies of [[gene]]s: meiotic division I is paused so that the oocyte grows while it contains two diploid chromosome sets. Some species produce many extra copies of genes, such as amphibians, which may have up to 1 or 2 million copies. A complementary mechanism is partly dependent on syntheses of other cells. In amphibians, birds, and insects, yolk is made by the liver (or its equivalent) and secreted into the [[blood]]. Neighboring [[accessory cell]]s in the ovary can also provide nutritive help of two types. In some invertebrates some oogonia become [[nurse cell]]s. These cells are connected by cytoplasmic bridges with oocytes. The nurse cells of insects provide oocytes macromolecules such as proteins and mRNA. Follicular granulosa cells are the second type of accessory cells in the ovary in both invertebrates and vertebrates. They form a layer around the oocyte and nourish them with small molecules, no macromolecules, but eventually their smaller precursor molecules, by [[gap junction]]s.{{citation needed|date=December 2011}}

===Mutation and DNA repair===

The [[mutation]] frequency of female [[germline]] cells in mice is about 5-fold lower than that of [[somatic cell]]s, according to one study.<ref name="pmid23153565">{{cite journal | vauthors = Murphey P, McLean DJ, McMahan CA, Walter CA, McCarrey JR | title = Enhanced genetic integrity in mouse germ cells | journal = Biology of Reproduction | volume = 88 | issue = 1 | pages = 6 | date = January 2013 | pmid = 23153565 | pmc = 4434944 | doi = 10.1095/biolreprod.112.103481 }}</ref>

The mouse [[oocyte]] in the [[dictyate]] (prolonged diplotene) stage of [[meiosis]] actively repairs [[DNA damage (naturally occurring)|DNA damage]], whereas [[DNA repair]] was not detected in the pre-dictyate ([[leptotene]], [[zygotene]] and [[pachytene]]) stages of meiosis.<ref name="pmid3380109">{{cite journal | vauthors = Guli CL, Smyth DR | title = UV-induced DNA repair is not detectable in pre-dictyate oocytes of the mouse | journal = Mutation Research | volume = 208 | issue = 2 | pages = 115–119 | date = June 1988 | pmid = 3380109 | doi = 10.1016/s0165-7992(98)90010-0 }}</ref>  The long period of meiotic arrest at the four [[chromatid]] dictyate stage of meiosis may facilitate [[homologous recombination|recombination]]al repair of DNA damages.<ref name="pmid9778439">{{cite journal | vauthors = Mira A | title = Why is meiosis arrested? | journal = Journal of Theoretical Biology | volume = 194 | issue = 2 | pages = 275–287 | date = September 1998 | pmid = 9778439 | doi = 10.1006/jtbi.1998.0761 | bibcode = 1998JThBi.194..275M }}</ref>

==Spermatogenesis==

[[Mammal]]ian [[spermatogenesis]] is representative for most animals. In human males, spermatogenesis begins at puberty in [[seminiferous tubules]] in the testicles and go on continuously. Spermatogonia are immature germ cells. They proliferate continuously by mitotic divisions around the outer edge of the [[seminiferous tubule]]s, next to the [[basal lamina]]. Some of these cells stop proliferation and differentiate into primary spermatocytes. After they proceed through the first meiotic division, two secondary spermatocytes are produced. The two secondary spermatocytes undergo the second meiotic division to form four haploid spermatids. These spermatids differentiate morphologically into sperm by nuclear condensation, ejection of the cytoplasm and formation of the [[acrosome]] and [[flagellum]].{{citation needed|date=December 2011}}

The developing male germ cells do not complete [[cytokinesis]] during spermatogenesis. Consequently, cytoplasmic bridges exist during interphase to ensure connection between the clones of differentiating daughter cells. These bridges are called a [[syncytium]], and feature a [[TEX14]] and [[KIF23]] ring in their centre.<ref>{{cite journal | vauthors = Greenbaum MP, Yan W, Wu MH, Lin YN, Agno JE, Sharma M, Braun RE, Rajkovic A, Matzuk MM | display-authors = 6 | title = TEX14 is essential for intercellular bridges and fertility in male mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 13 | pages = 4982–4987 | date = March 2006 | pmid = 16549803 | pmc = 1458781 | doi = 10.1073/pnas.0505123103 | bibcode = 2006PNAS..103.4982G | doi-access = free }}</ref><ref>{{cite journal | vauthors = Greenbaum MP, Iwamori N, Agno JE, Matzuk MM | title = Mouse TEX14 is required for embryonic germ cell intercellular bridges but not female fertility | journal = Biology of Reproduction | volume = 80 | issue = 3 | pages = 449–457 | date = March 2009 | pmid = 19020301 | pmc = 2805395 | doi = 10.1095/biolreprod.108.070649 }}</ref> In this way the haploid cells are supplied with all the products of a complete diploid [[genome]]. Sperm that carry a [[Y chromosome]], for example, are supplied with essential molecules that are encoded by genes on the [[X chromosome]].{{citation needed|date=December 2011}}

Success of germ cell proliferation and differentiation is also ensured by a balance between germ cell development and programmed cell death. Identification of «death triggering signals» and corresponding receptor proteins is important for the fertilization potential of males. Apoptosis in germ cells can be induced by variety of naturally occurring toxicant. Receptors belonging to the taste 2 family are specialized to detect bitter compounds including extremely toxic alkaloids. So taste receptors play a functional role for controlling apoptosis in male reproductive tissue.<ref>{{cite journal | vauthors = Luddi A, Governini L, Wilmskötter D, Gudermann T, Boekhoff I, Piomboni P | title = Taste Receptors: New Players in Sperm Biology | journal = International Journal of Molecular Sciences | volume = 20 | issue = 4 | page = 967 | date = February 2019 | pmid = 30813355 | pmc = 6413048 | doi = 10.3390/ijms20040967 | doi-access = free }}</ref>

===Mutation and DNA repair===

The mutation frequencies for cells throughout the different stages of [[spermatogenesis]] in mice is similar to that in female germline cells, that is  5 to 10-fold lower than the mutation frequency in somatic cells<ref name="pmid9707592">{{cite journal | vauthors = Walter CA, Intano GW, McCarrey JR, McMahan CA, Walter RB | title = Mutation frequency declines during spermatogenesis in young mice but increases in old mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 17 | pages = 10015–10019 | date = August 1998 | pmid = 9707592 | pmc = 21453 | doi = 10.1073/pnas.95.17.10015 | doi-access = free | bibcode = 1998PNAS...9510015W }}</ref><ref name="pmid23153565" />  Thus low mutation frequency is a feature of germline cells in both sexes. 
Homologous recombinational repair of double-strand breaks occurs in mouse during sequential stages of spermatogenesis, but is most prominent in [[spermatocyte]]s.<ref name="pmid9778439"/> The lower frequencies of mutation in germ cells compared to somatic cells appears to be due to more efficient removal of DNA damages by repair processes including homologous recombination repair during meiosis.<ref>Bernstein H, Byerly HC, Hopf FA, Michod RE. Genetic damage, mutation, and the evolution of sex. Science. 1985 Sep 20;229(4719):1277-81. doi: 10.1126/science.3898363. PMID 3898363</ref>  Mutation frequency during spermatogenesis increases with age.<ref name="pmid9707592" />  The mutations in spermatogenic cells of old mice include an increased prevalence of [[transversion]] mutations compared to young and middle-aged mice.<ref name="pmid15084311">{{cite journal | vauthors = Walter CA, Intano GW, McMahan CA, Kelner K, McCarrey JR, Walter RB | title = Mutation spectral changes in spermatogenic cells obtained from old mice | journal = DNA Repair | volume = 3 | issue = 5 | pages = 495–504 | date = May 2004 | pmid = 15084311 | doi = 10.1016/j.dnarep.2004.01.005 }}</ref>

==Diseases==
[[Germ cell tumor]] is a rare [[cancer]] that can affect people at all ages. As of 2018, germ cell tumors account for 3% of all cancers in children and adolescents 0–19 years old.<ref>{{Cite web|url=https://curesearch.org/Number-of-Diagnoses|title=Number of Diagnoses {{!}} CureSearch|website=CureSearch for Children's Cancer|date=22 September 2014 |language=en-US|access-date=2019-09-27}}</ref>

Germ cell tumors are generally located in the [[gonad]]s but can also appear in the [[abdomen]], [[pelvis]], [[mediastinum]], or [[brain]]. Germ cells migrating to the gonads may not reach that intended destination and a tumor can grow wherever they end up, but the exact cause is still unknown. These tumors can be [[benign tumor|benign]] or [[malignant tumor|malignant]].<ref>{{cite web | title = Germ cell tumors| vauthors = Olson T |publisher=CureSearch.org |year=2006 |url= http://www.curesearch.org/for_parents_and_families/newlydiagnosed/article.aspx?ArticleId=3190&StageID=1&TopicId=1&Level=1 }}</ref>

On arrival at the gonad, primordial germ cells that do not properly differentiate may produce [[germ cell tumor]]s of the [[ovary]] or [[Testicle|testis]] in a [[mouse model]].<ref>{{cite journal | vauthors = Nicholls PK, Schorle H, Naqvi S, Hu YC, Fan Y, Carmell MA, Dobrinski I, Watson AL, Carlson DF, Fahrenkrug SC, Page DC | display-authors = 6 | title = Mammalian germ cells are determined after PGC colonization of the nascent gonad | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 51 | pages = 25677–25687 | date = December 2019 | pmid = 31754036 | pmc = 6925976 | doi = 10.1073/pnas.1910733116 | bibcode = 2019PNAS..11625677N | doi-access = free }}</ref>

==Induced differentiation==
Inducing differentiation of certain cells to germ cells has many applications. One implication of induced differentiation is that it may allow for the eradication of male and female factor infertility. Furthermore, it would allow same-sex couples to have biological children if sperm could be produced from female cells or if eggs could be produced from male cells. Efforts to create sperm and eggs from skin and embryonic stem cells were pioneered by Hayashi and Saitou's research group at Kyoto University.<ref>{{cite journal | vauthors = Hayashi K, Ogushi S, Kurimoto K, Shimamoto S, Ohta H, Saitou M | title = Offspring from oocytes derived from in vitro primordial germ cell-like cells in mice | journal = Science | volume = 338 | issue = 6109 | pages = 971–975 | date = November 2012 | pmid = 23042295 | doi = 10.1126/science.1226889 | s2cid = 6196269 | bibcode = 2012Sci...338..971H | doi-access = free }}</ref> These researchers produced primordial germ cell-like cells (PGLCs) from embryonic stem cells (ESCs) and skin cells in vitro.

Hayashi and Saitou's group was able to promote the differentiation of embryonic stem cells into PGCs with the use of precise timing and bone morphogenetic protein 4 (Bmp4). Upon succeeding with embryonic stem cells, the group was able to successfully promote the differentiation of induced pluripotent stem cells (iPSCs) into PGLCs. These primordial germ cell-like cells were then used to create spermatozoa and oocytes.<ref>{{cite journal | vauthors = Cyranoski D | title = Stem cells: Egg engineers | journal = Nature | volume = 500 | issue = 7463 | pages = 392–394 | date = August 2013 | pmid = 23969442 | doi = 10.1038/500392a | doi-access =  | bibcode = 2013Natur.500..392C | s2cid = 34253 }}</ref>

Efforts for human cells are less advanced due to the fact that the PGCs formed by these experiments are not always viable. In fact Hayashi and Saitou's method is only one third as effective as current in vitro fertilization methods, and the produced PGCs are not always functional. Furthermore, not only are the induced PGCs not as effective as naturally occurring PGCs, but they are also less effective at erasing their epigenetic markers when they differentiate from iPSCs or ESCs to PGCs.

There are also other applications of induced differentiation of germ cells. Another study showed that culture of [[human embryonic stem cell]]s in mitotically inactivated [[porcine ovarian fibroblast]]s (POF) causes differentiation into germ cells, as evidenced by [[gene expression]] analysis.<ref>{{cite journal | vauthors = Richards M, Fong CY, Bongso A | title = Comparative evaluation of different in vitro systems that stimulate germ cell differentiation in human embryonic stem cells | journal = Fertility and Sterility | volume = 93 | issue = 3 | pages = 986–994 | date = February 2010 | pmid = 19064262 | doi = 10.1016/j.fertnstert.2008.10.030 | doi-access = free }}</ref>

== See also ==
* [[Germline development]]
* [[List of human cell types derived from the germ layers]]
* [[Germ cell tumor]]

== References ==
{{Reflist}}

== External links ==
{{Commons category|Germ cells}}
* {{MeshName|Germ+Cells}}
* [https://web.archive.org/web/20110415122814/http://php.med.unsw.edu.au/embryology/index.php?title=Primordial_Germ_Cell_Development Primordial Germ Cell Development]

{{Sex (biology)}}
{{Authority control}}

[[Category:Germ cells| ]]