# Gonocyte

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'''Gonocytes''' are the precursors of [spermatogonia](/source/spermatogonia) that differentiate in the [testis](/source/testis) from [primordial germ cells](/source/primordial_germ_cells) around week 7 of embryonic development and exist up until the postnatal period, when they become spermatogonia.<ref name="Culty-2009">{{Cite journal|last=Culty|first=Martine|date=2009|title=Gonocytes, the forgotten cells of the germ cell lineage|journal=Birth Defects Research Part C: Embryo Today: Reviews|language=en|volume=87|issue=1|pages=1–26|doi=10.1002/bdrc.20142|pmid=19306346|issn=1542-9768}}</ref> Germ cells operate as vehicles of inheritance by transferring genetic and epigenetic information from one generation to the next. Male fertility is centered around continual spermatogonia which is dependent upon a high stem cell population. Thus, the function and quality of a differentiated sperm cell is dependent upon the capacity of its originating spermatogonial stem cell (SSC).<ref name="Yang-2014">{{Citation|last1=Yang|first1=Qi-En|title=Chapter Nine - Spermatogonial Stem Cell Functions in Physiological and Pathological Conditions|date=2014-01-01|url=http://www.sciencedirect.com/science/article/pii/B9780124160224000093|journal=Current Topics in Developmental Biology|volume=107|pages=235–267|editor-last=Rendl|editor-first=Michael|series=Stem Cells in Development and Disease|publisher=Academic Press|language=en|doi=10.1016/b978-0-12-416022-4.00009-3|access-date=2020-04-28|last2=Oatley|first2=Jon M.|pmid=24439809|url-access=subscription}}</ref>

Gonocytes represent the [germ cell](/source/germ_cell)s undergoing the successive, short-term and migratory stages of development. This occurs between the time they inhabit the forming [gonad](/source/gonad)s on the [genital ridge](/source/genital_ridge) to the time they migrate to the [basement membrane](/source/basement_membrane) of the [seminiferous cords](/source/Seminiferous_tubule). Gonocyte development consists of several phases of cell [proliferation](/source/Cell_proliferation), [differentiation](/source/Cellular_differentiation), [migration](/source/Cell_migration) and [apoptosis](/source/apoptosis).<ref name="Culty-2009"/><ref name="Manku-2015">{{Cite journal|last1=Manku|first1=Gurpreet|last2=Culty|first2=Martine|title=Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges|journal=Reproduction|year=2015|volume=149|issue=3|pages=R139–R157|doi=10.1530/rep-14-0431|pmid=25670871|issn=1470-1626|doi-access=free}}</ref> The abnormal development of gonocytes leads to fertility-related diseases.<ref name="Loebenstein-2019">{{Cite journal|last1=Loebenstein|first1=Moshe|last2=Thorup|first2=Jorgen|last3=Cortes|first3=Dina|last4=Clasen-Linde|first4=Erik|last5=Hutson|first5=John M|last6=Li|first6=Ruili|title=Cryptorchidism, gonocyte development, and the risks of germ cell malignancy and infertility: A systematic review|journal=Journal of Pediatric Surgery|year=2019|volume=55|issue=7|pages=1201–1210|doi=10.1016/j.jpedsurg.2019.06.023|pmid=31327540|s2cid=198134800 |issn=0022-3468}}</ref>

They are also identified as prespermatogonia, prospermatogonia and primitive germ cells, although gonocyte is most common.<ref name="Gaskell-2004">{{Cite journal|last1=Gaskell|first1=Terri L.|last2=Esnal|first2=Arantza|last3=Robinson|first3=Lynn L.L.|last4=Anderson|first4=Richard A.|last5=Saunders|first5=Philippa T.K.|date=2004-12-01|title=Immunohistochemical Profiling of Germ Cells Within the Human Fetal Testis: Identification of Three Subpopulations|journal=Biology of Reproduction|volume=71|issue=6|pages=2012–2021|doi=10.1095/biolreprod.104.028381|pmid=15317684|issn=0006-3363|doi-access=free}}</ref>

== History ==
Gonocytes are described as large and spherical, with a prominent nucleus and two [nucleoli](/source/nucleoli).<ref name="Culty-2009"/> The term, gonocyte, was created in 1957 by Canadian scientists Yves Clermont and Bernard Perey.<ref name="Culty-2013">{{Cite journal|last=Culty|first=Martine|date=2013-08-01|title=Gonocytes, from the Fifties to the Present: Is There a Reason to Change the Name?|journal=Biology of Reproduction|language=en|volume=89|issue=2|page=46|doi=10.1095/biolreprod.113.110544|pmid=23843237|issn=0006-3363|doi-access=free}}</ref> They considered it essential to study the origin of spermatogonia and carried out a study on rats to investigate this.<ref>{{Cite journal|last1=Clermont|first1=Yves|last2=Perey|first2=Bernard|date=1957|title=Quantitative study of the cell population of the seminiferous tubules in immature rats|journal=American Journal of Anatomy|language=en|volume=100|issue=2|pages=241–267|doi=10.1002/aja.1001000205|pmid=13435229|issn=1553-0795}}</ref> In 1987, Clermont referred to ''gonocytes'' as the cells that differentiate into [type A spermatogonia](/source/type_A_spermatogonia), which differentiate into type B spermatogonia and [spermatocytes](/source/spermatocytes).<ref name="Culty-2013"/>

Very few studies used gonocytes to also refer to the female germ cells in the ovarium primordium.<ref name="Culty-2013"/> The specification of gonocytes to be confined to male germ cells occurred after foundational differences between the mechanisms of male and female fetal germ cells were uncovered. Some scientists prefer the terms "prospermatogonia" and "prespermatogonia" for their functional clarity.<ref name="Gaskell-2004"/><ref name="Culty-2013"/>

Later studies found that the process from primordial germ cell to spermatogonial development is gradual, without clear gene expression markers to distinguish the precursor cells.<ref name="Culty-2013"/> A 2006 study found that some gonocytes differentiate straight into committed spermatogonia (type B) rather than spermatogonial stem cells (type A).<ref name="Culty-2009"/>

== Origin of spermatogonial stem cell pool ==
Gonocytes are long-lived precursor germ cells responsible for the production of spermatogonial stem cells (SSCs). Gonocytes relate to both fetal and neonatal germ cells from the point at which they enter the testis primordial until they reach the base membrane at the seminiferous cords and differentiate. At the time of gastrulation, certain cells are set aside for later gamete development. These cells are called post migratory germ cells (PGCs). The gonocyte population develops from the post migratory germ cells (PGCs) around embryonic day (ED) 15.<ref>{{Cite journal|last1=Yoshioka|first1=Hirotaka|last2=McCarrey|first2=John R.|last3=Yamazaki|first3=Yukiko|date=2009-04-01|title=Dynamic Nuclear Organization of Constitutive Heterochromatin During Fetal Male Germ Cell Development in Mice1|journal=Biology of Reproduction|language=en|volume=80|issue=4|pages=804–812|doi=10.1095/biolreprod.108.072603|issn=0006-3363|pmc=2804833|pmid=19129513}}</ref> At this point of development, PGCs become dormant and remain inactivated until birth. Shortly after birth, the cell cycle continues and the production of postnatal spermatogonia commences.<ref>{{Cite journal|last1=van Dissel-Emiliani|first1=F. M. F.|last2=de Boer-Brouwer|first2=M.|last3=Spek|first3=E. R.|last4=van der Donk|first4=J. A.|last5=de Rooij|first5=D. G.|date=1993-07-01|title=Survival and proliferation of rat gonocytes in vitro|journal=Cell and Tissue Research|language=en|volume=273|issue=1|pages=141–147|doi=10.1007/BF00304621|pmid=8364957|s2cid=27040219|issn=1432-0878}}</ref> Gonocytes migrate to the basement membrane to proliferate. Gonocytes that do not migrate undergo apoptosis and are cleared from the seminiferous epithelium.<ref>{{Cite journal|last1=Roosen-Runge|first1=Edward C.|last2=Leik|first2=Jean|date=March 1968|title=Gonocyte degeneration in the postnatal male rat|journal=American Journal of Anatomy|language=en|volume=122|issue=2|pages=275–299|doi=10.1002/aja.1001220208|pmid=5665153|issn=0002-9106}}</ref> Spermatogonia are formed in infancy and differentiate throughout adult life.<ref>{{Cite journal|last1=Manku|first1=Gurpreet|last2=Culty|first2=Martine|date=2015-03-01|title=Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges|url=https://rep.bioscientifica.com/view/journals/rep/149/3/R139.xml|journal=Reproduction|language=en-US|volume=149|issue=3|pages=R139–R157|doi=10.1530/REP-14-0431|pmid=25670871|issn=1741-7899|doi-access=free}}</ref>

== Formation of spermatogonial lineage ==
There are currently two proposed models for the formation of the spermatogonial lineage during neonatal development. Both models theorize that the gonocyte population develops from a subset of post migratory germ cells (PGCs) but, differ in the proposed subsets of derived gonocytes. One of the models proposes that the PGCs give rise to a single subset of pluripotent gonocytes that either become SSCs from which progenitors then arise or differentiate into type A spermatogonia directly. The other model proposes that the PGCs give rise to multiple predetermined subsets of gonocytes that produce the foundational SSC pool, initial progenitor spermatogonial population, and initial differentiating type A spermatogonia.<ref name="Yang-2014"/>

== Development ==
The development of germ cells can be divided into two phases. The first phases involves the fetal and neonatal phases of germ cell development that lead to the formation of the SSCs. The second phase is [spermatogenesis](/source/spermatogenesis), which is a cycle of regulated [mitosis](/source/mitosis), [meiosis](/source/meiosis) and differentiation (via [spermiogenesis](/source/spermiogenesis)) leading to the production of mature [spermatozoa](/source/Spermatozoon), also known as sperm cells.<ref name="Culty-2009"/><ref name="de Rooij-2001">{{Cite journal|last=de Rooij|first=DG|date=2001-03-01|title=Proliferation and differentiation of spermatogonial stem cells|journal=Reproduction|volume=121|issue=3|pages=347–354|doi=10.1530/rep.0.1210347|pmid=11226060|issn=1470-1626|doi-access=free}}</ref><ref>{{Cite journal|title=All You Wanted to Know About Spermatogonia but Were Afraid to Ask|last1=Dg|first1=de Rooij|last2=Ld|first2=Russell|journal=Journal of Andrology|year=2000|volume=21|issue=6|pages=776–98|doi=10.1002/j.1939-4640.2000.tb03408.x |language=en|pmid=11105904|s2cid=11396277 }}</ref>

Gonocytes are functionally present during the first phase of germ cell maturation and development.<ref name="Manku-2015"/><ref name="de Rooij-2001" /> This period consists of the primordial germ cells (PGC), the initial cells that commence germ cell development in the [embryo](/source/embryo),<ref>{{Cite journal|last1=Fujimoto|first1=Toyoaki|last2=Miyayama|first2=Yukihiko|last3=Fuyuta|first3=Masatoshi|title=The origin, migration and fine morphology of human primordial germ cells|journal=The Anatomical Record|year=1977|volume=188|issue=3|pages=315–329|doi=10.1002/ar.1091880305|pmid=900520|s2cid=24648958|issn=0003-276X}}</ref> and the gonocytes, which after being differentiated from PGCs, undergo regulated proliferation, differentiation, migration and apoptosis to produce the SSCs.<ref name="Culty-2009" /><ref name="Manku-2015" /> Gonocytes therefore correspond to the developmental stages between the PGCs and SSCs.

=== Formation ===
Gonocytes are formed from the differentiation of PGCs.<ref name="Manku-2015" /> [Embryonic cells](/source/Cleavage_(embryo)) initiate germ cell development in the proximal [epiblast](/source/epiblast) located near the extra-embryonic [ectoderm](/source/ectoderm) by the release of [bone morphogenetic protein 4](/source/bone_morphogenetic_protein_4) (BMP4) and [BMP8b](/source/Bone_morphogenetic_protein_8B). These proteins specify embryonic cells into PGCs expressing the genes [PRDM1](/source/PRDM1) and PRDM14 at embryonic day (E) 6.25. The PGCs which are positively [stain](/source/stain)ed by [alkaline phosphatase](/source/alkaline_phosphatase) and expressing Stella at E7.25 are also specified.<ref>{{Cite journal|last=Saitou|first=Mitinori|title=Germ cell specification in mice|journal=Current Opinion in Genetics & Development|year=2009|volume=19|issue=4|pages=386–395|doi=10.1016/j.gde.2009.06.003|pmid=19616424|issn=0959-437X}}</ref><ref>{{Cite journal|last1=Lawson|first1=K. A.|last2=Dunn|first2=N. R.|last3=Roelen|first3=B. A.J.|last4=Zeinstra|first4=L. M.|last5=Davis|first5=A. M.|last6=Wright|first6=C. V.E.|last7=Korving|first7=J. P.W.F.M.|last8=Hogan|first8=B. L.M.|date=1999-02-15|title=Bmp4 is required for the generation of primordial germ cells in the mouse embryo|journal=Genes & Development|volume=13|issue=4|pages=424–436|doi=10.1101/gad.13.4.424|pmid=10049358|pmc=316469|issn=0890-9369}}</ref> In between E7.5 and E12.5, these PGCs migrate towards the [genital ridge](/source/Gonadal_ridge), where they form the [testicular](/source/Testes) cords, via the [cytokine](/source/cytokine) interactions of the [CXCR4](/source/CXCR4) and [c-Kit](/source/C_Kit) membrane receptors and their ligands [SDF1](/source/Stromal_cell-derived_factor_1) and SCF respectively.<ref>{{Cite journal|title=Molecular Control of Rodent Spermatogenesis|last1=Sz|first1=Jan|last2=G|first2=Hamer|language=en|pmid=22366765|last3=S|first3=Repping|last4=Dg|first4=de Rooij|last5=Am|first5=van Pelt|last6=Tl|first6=Vormer|journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease|year=2012|volume=1822|issue=12|pages=1838–50|doi=10.1016/j.bbadis.2012.02.008|doi-access=free}}</ref><ref name="De Felici-2009">{{Cite journal|last=De Felici|first=Massimo|date=2009|title=Primordial germ cell biology at the beginning of the XXI Century|journal=The International Journal of Developmental Biology|volume=53|issue=7|pages=891–894|doi=10.1387/ijdb.082815mf|pmid=19598110|issn=0214-6282|doi-access=free}}</ref><ref>{{Cite journal|last1=Raz|first1=E.|last2=Mahabaleshwar|first2=H.|date=2009-03-20|title=Chemokine signaling in embryonic cell migration: a fisheye view|journal=Development|volume=136|issue=8|pages=1223–1229|doi=10.1242/dev.022418|pmid=19304885|issn=0950-1991|doi-access=free}}</ref> During this migratory period, PGCs undergo [epigenetic reprogramming](/source/Reprogramming) through [genome](/source/genome)-wide [DNA demethylation](/source/DNA_demethylation).<ref name="De Felici-2009" /> Once resident in the genital ridge, these germ cells and surrounding supporting cells undergo [sex determination](/source/Sex-determination_system) driven by the expression of the [SRY](/source/SRY) gene.<ref>{{Cite journal|last=Jameson, Samantha A. Natarajan, Anirudh Cool, Jonah DeFalco, Tony Maatouk, Danielle M. Mork, Lindsey Munger, Steven C. Capel, Blanche|title=Temporal Transcriptional Profiling of Somatic and Germ Cells Reveals Biased Lineage Priming of Sexual Fate in the Fetal Mouse Gonad|journal=PLOS Genetics|publisher=Public Library of Science|year=2012|volume=8|issue=3|article-number=e1002575|doi=10.1371/journal.pgen.1002575|pmid=22438826|pmc=3305395|oclc=841508977 |doi-access=free }}</ref> It is only after these developmental steps that the germ cells present in the developed testicular cords are identified as gonocytes.<ref name="Manku-2015" />

=== Proliferation ===
In order to provide the long-term production of sperm, gonocytes undergo proliferation to produce a populate pool of SSCs.<ref name="Manku-2015" /><ref name="de Rooij-2001" /><ref name="Loebenstein-2019"/> Once enclosed by [Sertoli cell](/source/Sertoli_cell)s to form the testicular cords, gonocytes undergo a succession of differing fetal and neonatal periods of mitosis, with a phase of quiescence in between.<ref name="Culty-2009" /> The mitotic activity that occurs in the neonatal period is necessary for the migration of gonocytes to the basement membrane of the seminiferous cords in order to differentiate into the SSCs.<ref name="Culty-2009" /><ref name="Manku-2015" /> As many populations of gonocytes are in different stages of development, mitotic and quiescent gonocytes coexist in neonatal developing [testes](/source/Testicle).<ref name="Culty-2013"/>

Proliferation in fetal and neonatal gonocytes is differently regulated. [Retinoic acid](/source/Retinoic_acid) (RA), the [bioactive](/source/Bioactive_compound) [metabolite](/source/metabolite) of [retinal](/source/retinal), is a [morphogen](/source/morphogen) shown to modulate fetal gonocyte proliferation. Investigation of fetal gonocyte activity in [organ culture](/source/organ_culture)s recorded RA to slightly stimulate proliferation.<ref name="Livera-2002">{{Cite journal|last=Livera|first=G|date=2002-08-01|title=Regulation and perturbation of testicular functions by vitamin A|journal=Reproduction|volume=124|issue=2|pages=173–180|doi=10.1530/reprod/124.2.173|pmid=12141930|issn=1470-1626|doi-access=free}}</ref><ref name="Busada-2016">{{Cite journal|last1=Busada|first1=Jonathan T.|last2=Geyer|first2=Christopher B.|date=2016-01-01|title=The Role of Retinoic Acid (RA) in Spermatogonial Differentiation1|journal=Biology of Reproduction|volume=94|issue=1|page=10|doi=10.1095/biolreprod.115.135145|pmid=26559678|pmc=4809555|issn=0006-3363}}</ref> Moreover, RA inhibited differentiation by stopping the fetal gonocytes from entering mitotic arrest while simultaneously triggering apoptosis. RA, by decreasing the overall fetal gonocyte population via apoptosis, is speculated to allow the elimination of [mutated](/source/Mutation) and dysfunctional germ cells.<ref name="Busada-2016" /> The activation of [protein kinase C](/source/protein_kinase_C) by [phorbol ester PMA](/source/12-O-Tetradecanoylphorbol-13-acetate) also decreased fetal gonocyte mitotic activity.<ref>{{Cite journal|last1=Boulogne|first1=Barbara|last2=Habert|first2=Ren|last3=Levacher|first3=Christine|date=2003-04-15|title=Regulation of the proliferation of cocultured gonocytes and sertoli cells by retinoids, triiodothyronine, and intracellular signaling factors: Differences between fetal and neonatal cells|journal=Molecular Reproduction and Development|volume=65|issue=2|pages=194–203|doi=10.1002/mrd.10311|pmid=12704731|s2cid=25507768|issn=1040-452X}}</ref>

There are a number of factors that influence neonatal gonocyte proliferation, including [17β‐estradiol](/source/Estradiol) (E2), [Leukemia inhibitory factor](/source/Leukemia_inhibitory_factor) (LIF), [platelet-derived growth factor (PDGF)](/source/Platelet-derived_growth_factor)-BB, and RA. The production of PDGF-BB and E2 by surrounding Sertoli cells activate their respective receptors on neonatal gonocytes, triggering proliferation via an interactive, crosstalk mechanism.<ref name="Basciani-2008">{{Cite journal|last1=Basciani|first1=Sabrina|last2=De Luca|first2=Gabriele|last3=Dolci|first3=Susanna|last4=Brama|first4=Marina|last5=Arizzi|first5=Mario|last6=Mariani|first6=Stefania|last7=Rosano|first7=Giuseppe|last8=Spera|first8=Giovanni|last9=Gnessi|first9=Lucio|title=Platelet-Derived Growth Factor Receptor β-Subtype Regulates Proliferation and Migration of Gonocytes|journal=Endocrinology|year=2008|volume=149|issue=12|pages=6226–6235|doi=10.1210/en.2008-0349|pmid=18687785|issn=0013-7227|doi-access=free}}</ref><ref>{{Cite journal|last1=Thuillier|first1=Raphael|last2=Mazer|first2=Monty|last3=Manku|first3=Gurpreet|last4=Boisvert|first4=Annie|last5=Wang|first5=Yan|last6=Culty|first6=Martine|date=2010-05-01|title=Interdependence of Platelet-Derived Growth Factor and Estrogen-Signaling Pathways in Inducing Neonatal Rat Testicular Gonocytes Proliferation1|journal=Biology of Reproduction|volume=82|issue=5|pages=825–836|doi=10.1095/biolreprod.109.081729|pmid=20089883|pmc=2857630|issn=0006-3363}}</ref> The regulation of LIF is speculated to allow gonocytes to become sensitive to Sertoli cell factors that trigger proliferation, such as PDGF-BB and E2.<ref>{{Cite journal|last=Wang, Peng Suo, Li-Juan Wang, Yan-Feng Shang, Hua Li, Guang-Xuan Hu, Jian-Hong Li, Qing-Wang|title=Effects of GDNF and LIF on mouse spermatogonial stem cells proliferation in vitro|journal=Cytotechnology|date=2013-07-30|volume=66|issue=2|pages=309–16|publisher=Springer Netherlands|doi=10.1007/s10616-013-9574-2|pmid=23896701|pmc=3918261|oclc=914239197}}</ref> Compared to fetal gonocytes, RA exerts a similar functional role in neonatal gonocytes; It simultaneously stimulates proliferation and apoptosis for regulation of gonocyte and future SSCs population.<ref name="Manku-2015" /><ref name="Livera-2002" /><ref name="Busada-2016" />

=== Migration ===
The migration of gonocytes to the basement membrane of the seminiferous cords is necessary for their differentiation into SSCs.<ref name="Culty-2009" /><ref name="de Rooij-2001" /><ref name="Loebenstein-2019" /> This process is regulated by different factors.

Various studies provide comprehensive comparison of the expression of c-Kit on the membrane of cells and migratory-related behavior, for example PGCs.<ref>{{Cite journal|last1=Zhang|first1=Lei|last2=Tang|first2=Jiangjing|last3=Haines|first3=Christopher J|last4=Feng|first4=Huai|last5=Lai|first5=Liangxue|last6=Teng|first6=Xiaoming|last7=Han|first7=Yibing|date=2013|title=c-kit expression profile and regulatory factors during spermatogonial stem cell differentiation|journal=BMC Developmental Biology|volume=13|issue=1|page=38|doi=10.1186/1471-213x-13-38|pmid=24161026|pmc=3871025|issn=1471-213X |doi-access=free }}</ref> Although c-Kit expression is evident in a small fraction of neonatal gonocytes,<ref>{{Cite journal |last=Prabhu |first=Sridurga |last2=Meistrich |first2=Marvin |last3=McLaughlin |first3=Eileen |last4=Roman |first4=Shaun |last5=Warne |first5=Sam |last6=Mendis |first6=Sirisha |last7=Itman |first7=Catherine |last8=Loveland |first8=Kate |author-link8=Kate Loveland |date=2006 |title=Expression of c-Kit receptor mRNA and protein in the developing, adult and irradiated rodent testis. |journal=Reproduction |publisher=Bio Scientifica Ltd |volume=131 |issue=3 |pages=489–99 |doi=10.1530/rep.1.00968 |oclc=696515509 |pmid=16514192 |doi-access=free}}</ref> they also express of [PDGF receptor](/source/Platelet-derived_growth_factor_receptor) beta (PDGFRβ) on their membrane to aid in their migration.<ref>{{Cite journal|last1=Wang|first1=Yan|last2=Culty|first2=Martine|date=2007-05-01|title=Identification and Distribution of a Novel Platelet-Derived Growth Factor Receptor β Variant: Effect of Retinoic Acid and Involvement in Cell Differentiation|journal=Endocrinology|volume=148|issue=5|pages=2233–2250|doi=10.1210/en.2006-1206|pmid=17303670|issn=0013-7227|doi-access=free}}</ref> Inhibition of PDGF receptors and c-Kit by [in vivo](/source/in_vivo) treatment of [imatinib](/source/imatinib), an inhibitory [drug](/source/drug), interrupted migration, leading to a number of gonocytes centrally located in the seminiferous cords.<ref name="Basciani-2008" />

The [ADAM-Integrin](/source/ADAM10)-[Tetraspanin](/source/Tetraspanin) complexes, which is a family of [protein](/source/protein)s, also mediate gonocyte migration. These complexes consist of various proteins that bind to integrins found on the basement membrane of the seminiferous cords and at locations where [spermatogonia](/source/Spermatogonium) normally reside, allowing the gonocyte to migrate and bind to the basement membrane.<ref>{{Cite journal|last1=Tres|first1=Laura L.|last2=Kierszenbaum|first2=Abraham L.|date=2005|title=The ADAM-integrin-tetraspanin complex in fetal and postnatal testicular cords|journal=Birth Defects Research Part C: Embryo Today: Reviews|volume=75|issue=2|pages=130–141|doi=10.1002/bdrc.20041|pmid=16035044|issn=1542-975X}}</ref>

=== Differentiation ===
thumb|Oxidation reactions required for retinol to become retinoic acid in the gonocyte cell
The differentiation of gonocytes to SSC only occur once the cells have established close contact with the basement membrane in the seminiferous cords.<ref name="Manku-2015" /><ref name="de Rooij-2001" /> RA is the best characterised activator of gonocyte differentiation.<ref name="Manku-2015" /> [De novo synthesis](/source/De_novo_synthesis) of RA involves [retinol](/source/retinol), the precursor to RA, being transported to the membrane receptor [STRA6](/source/Receptor_for_retinol_uptake_STRA6) by the [retinol-binding protein](/source/retinol-binding_protein) released by Sertoli cells. Binding of retinol to STRA6 [endocytoses](/source/Endocytosis) retinol into the cell, whereby it undergoes [oxidation reaction](/source/oxidation_reaction)s to form RA. RA is also directly transported from the surrounding Sertoli cells or the [vasculature](/source/Circulatory_system). RA internalization triggers a variety of pathways that modulate the differentiation, such as PDGF receptor [pathways](/source/Signal_transduction) and [Janus kinase 2](/source/Janus_kinase_2) (JAK2) signaling pathway.<ref name="Busada-2016" />

[Anti-Müllerian hormone](/source/Anti-M%C3%BCllerian_hormone) (AMH), a [glycoprotein](/source/glycoprotein) [gonadal hormone](/source/Sex_steroid) produced by Sertoli cells in early development, is the only [hormone](/source/hormone) to significantly increase the number of successfully differentiated gonocytes.<ref>{{Cite journal|last1=Wu|first1=Ray-Chang|last2=Zeng|first2=Yang|last3=Chen|first3=Yu-Fang|last4=Lanz|first4=Rainer B.|last5=Wu|first5=Mei-Yi|date=2017-03-16|title=Temporal-Spatial Establishment of Initial Niche for the Primary Spermatogonial Stem Cell Formation Is Determined by an ARID4B Regulatory Network|journal=Stem Cells|volume=35|issue=6|pages=1554–1565|doi=10.1002/stem.2597|pmid=28207192|pmc=5743547|issn=1066-5099}}</ref>

The timing of differentiation is regulated by [NOTCH signaling](/source/Notch_signaling_pathway).<ref name="Garcia-2013a">{{Cite journal|last1=Garcia|first1=Thomas Xavier|last2=Hofmann|first2=Marie-Claude|date=2013-08-15|title=NOTCH signaling in Sertoli cells regulates gonocyte fate|journal=Cell Cycle|volume=12|issue=16|pages=2538–2545|doi=10.4161/cc.25627|pmid=23907117|pmc=3865042|issn=1538-4101}}</ref> The functional components of the NOTCH signaling pathway are expressed and released by both developing and adult Sertoli cells.<ref name="Garcia-2013b">{{Cite journal|last1=Garcia|first1=Thomas Xavier|last2=DeFalco|first2=Tony|last3=Capel|first3=Blanche|last4=Hofmann|first4=Marie-Claude|title=Constitutive activation of NOTCH1 signaling in Sertoli cells causes gonocyte exit from quiescence|journal=Developmental Biology|year=2013|volume=377|issue=1|pages=188–201|doi=10.1016/j.ydbio.2013.01.031|pmid=23391689|pmc=3630254|issn=0012-1606}}</ref> Activation of the signaling pathway is crucial for gonocyte development as it triggers gonocytes to depart from quiescence and enter into differentiation. Over activation of the pathway allows effective inhibition of quiescence and gonocyte differentiation.<ref name="Garcia-2013a" /><ref name="Garcia-2013b" />

== Structure of gonocytes ==
Gonocytes are large cells with a spherical [euchromatic](/source/Euchromatin) [nucleus](/source/Cell_nucleus), two [nucleoli](/source/Nucleolus) and a surrounding, ring-like [cytosol](/source/cytosol).<ref name="Culty-2013" /><ref>{{Cite journal|last1=Gondos|first1=Bernard|last2=Hobel|first2=Calvin J.|date=1971|title=Ultrastructure of germ cell development in the human fetal testis|journal=Zeitschrift für Zellforschung und Mikroskopische Anatomie|volume=119|issue=1|pages=1–20|doi=10.1007/bf00330535|pmid=4327535|s2cid=13270700|issn=0302-766X}}</ref> Throughout the majority of their developmental period, gonocytes are structurally supported by the cytoplasmic extensions of surrounding Sertoli cells and are suspended by Sertoli cell nuclei from the basement membrane.<ref name="Culty-2013" /><ref name="Journal of Electron Microscopy-1976">{{Cite journal|date=1976|title=Gap Junctions of Lens Fiber Cells in Freeze-Fracture Replicas|journal=Journal of Electron Microscopy|doi=10.1093/oxfordjournals.jmicro.a049994|issn=1477-9986}}</ref><ref name="Manku-2015" /> Gonocytes are attached to Sertoli cells by [gap junction](/source/gap_junction)s,<ref name="Journal of Electron Microscopy-1976" /> [desmosome junctions](/source/Desmosome)<ref name="Manku-2015" /> and a number of different cell adhesion molecules such as [connexin 43](/source/GJA1), [PB-cadherin](/source/CDH3_(gene)) and [NCAM](/source/Neural_cell_adhesion_molecule)<ref name="Culty-2013" /> for regulation of [cell-to-cell communication](/source/Cell_communication).<ref name="Journal of Electron Microscopy-1976" /><ref name="Manku-2015" /> Gonocytes dissociate from these junctions and migrate so that the basal side of the cell is in close proximity with the basement membrane, where they undergo [phenotypic](/source/Phenotype) changes and take the appearance of spermatogonia.<ref name="Culty-2013" /><ref name="Manku-2015" />

== Diseases ==
Dysfunctional development in germ cells plays a significant role in fertility-related [disease](/source/disease)s.<ref name="Manku-2015" /><ref name="Loebenstein-2019" /> The development of PGCs to gonocytes, and gonocyte differentiation to SSCs is critical for adult [fertility](/source/fertility) and the defective growth often leads to [infertility](/source/infertility).<ref name="Manku-2015" />

=== Testicular cancer ===
[Testicular germ cell tumors](/source/Germ_cell_tumor), that occur primarily in young adults, are the consequent of preinvasive cells called [carcinoma in situ](/source/carcinoma_in_situ) (CIS).<ref name="Baroni-2019">{{Cite journal|last1=Baroni|first1=Tiziano|last2=Arato|first2=Iva|last3=Mancuso|first3=Francesca|last4=Calafiore|first4=Riccardo|last5=Luca|first5=Giovanni|date=2019-06-06|title=On the Origin of Testicular Germ Cell Tumors: From Gonocytes to Testicular Cancer|journal=Frontiers in Endocrinology|volume=10|page=343|doi=10.3389/fendo.2019.00343|pmid=31244770|pmc=6563414|issn=1664-2392|doi-access=free }}</ref> The development of CIS is due to fetal germ cells, such as gonocytes, arrested in quiescence and unable to properly differentiate.<ref name="Baroni-2019" /><ref name="Gj-2009">{{Cite journal|title=Recent Developments in Testicular Germ Cell Tumor Research|last1=Gj|first1=van de Geijn|last2=R|first2=Hersmus|language=en|pmid=19306344|last3=Lh|first3=Looijenga|journal=Birth Defects Research Part C: Embryo Today: Reviews|year=2009|volume=87|issue=1|pages=96–113|doi=10.1002/bdrc.20140|url=https://pure.eur.nl/ws/files/46836350/Geijn_et_al-2009-Birth_Defects_Research_Part_C__Embryo_Today__Reviews-1-.pdf }}</ref> This leads to [malignant transformation](/source/malignant_transformation) of the germ cells until it becomes an overt germ cell [cancer](/source/cancer) after [puberty](/source/puberty).<ref name="Gj-2009" />

=== Cryptorchidism ===
[Cryptorchidism](/source/Cryptorchidism), also known as undescended testis, is a common [birth defect](/source/birth_defect) affecting [male genital](/source/Sex_organ) formation.<ref>{{Citation|last1=Leslie|first1=Stephen W.|title=Cryptorchidism|date=2020|url=https://www.ncbi.nlm.nih.gov/books/NBK470270/|work=StatPearls|publisher=StatPearls Publishing|pmid=29261861|access-date=2020-05-21|last2=Sajjad|first2=Hussain|last3=Villanueva|first3=Carlos A.}}</ref> Individuals diagnosed with cryptorchidism are often at risk of [testicular cancer](/source/testicular_cancer) and infertility due to dysfunction in the development of the neonatal germ cells, in particular, the disruption of the differentiation of gonocytes into adult dark-spermatogonia.<ref name="Loebenstein-2019" /> It is proposed that this dysfunction is a product of heat stress caused by the undescended testes remaining in the [abdomen](/source/abdomen) and unable to regulate its temperature which is often accomplished by the [scrotum](/source/scrotum).<ref>{{Cite journal|last1=Fawzy|first1=Fatma|last2=Hussein|first2=Amr|last3=Eid|first3=Mostafa Mahmoud|last4=El Kashash|first4=Ahmed Mahmoud|last5=Salem|first5=Hosni Khairy|date=2015-12-22|title=Cryptorchidism and Fertility|journal=Clinical Medicine Insights. Reproductive Health|volume=9|pages=39–43|doi=10.4137/CMRH.S25056|issn=1179-5581|pmc=4689328|pmid=26740750}}</ref>

== References ==
{{Reflist}}
{{Reproductive physiology}}

Category:Developmental biology
Category:Animal reproductive system
Category:Germ cells

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Adapted from the Wikipedia article [Gonocyte](https://en.wikipedia.org/wiki/Gonocyte) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Gonocyte?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.