Gonocytes are the precursors ofspermatogonia that differentiate in thetestis fromprimordial germ cells around week 7 of embryonic development and exist up until the postnatal period, when they become spermatogonia.[1] 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).[2]
Gonocytes represent thegerm cells undergoing the successive, short-term and migratory stages of development. This occurs between the time they inhabit the forminggonads on thegenital ridge to the time they migrate to thebasement membrane of theseminiferous cords. Gonocyte development consists of several phases of cellproliferation,differentiation,migration andapoptosis.[1][3] The abnormal development of gonocytes leads to fertility-related diseases.[4]
They are also identified as prespermatogonia, prospermatogonia and primitive germ cells, although gonocyte is most common.[5]
Gonocytes are described as large and spherical, with a prominent nucleus and twonucleoli.[1] The term, gonocyte, was created in 1957 by Canadian scientists Yves Clermont and Bernard Perey.[6] They considered it essential to study the origin of spermatogonia and carried out a study on rats to investigate this.[7] In 1987, Clermont referred togonocytes as the cells that differentiate intotype A spermatogonia, which differentiate into type B spermatogonia andspermatocytes.[6]
Very few studies used gonocytes to also refer to the female germ cells in the ovarium primordium.[6] 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.[5][6]
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.[6] A 2006 study found that some gonocytes differentiate straight into committed spermatogonia (type B) rather than spermatogonial stem cells (type A).[1]
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.[8] 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.[9] Gonocytes migrate to the basement membrane to proliferate. Gonocytes that do not migrate undergo apoptosis and are cleared from the seminiferous epithelium.[10] Spermatogonia are formed in infancy and differentiate throughout adult life.[11]
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.[2]
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 isspermatogenesis, which is a cycle of regulatedmitosis,meiosis and differentiation (viaspermiogenesis) leading to the production of maturespermatozoa, also known as sperm cells.[1][12][13]
Gonocytes are functionally present during the first phase of germ cell maturation and development.[3][12] This period consists of the primordial germ cells (PGC), the initial cells that commence germ cell development in theembryo,[14] and the gonocytes, which after being differentiated from PGCs, undergo regulated proliferation, differentiation, migration and apoptosis to produce the SSCs.[1][3] Gonocytes therefore correspond to the developmental stages between the PGCs and SSCs.
Gonocytes are formed from the differentiation of PGCs.[3]Embryonic cells initiate germ cell development in the proximalepiblast located near the extra-embryonicectoderm by the release ofbone morphogenetic protein 4 (BMP4) andBMP8b. These proteins specify embryonic cells into PGCs expressing the genesPRDM1 and PRDM14 at embryonic day (E) 6.25. The PGCs which are positivelystained byalkaline phosphatase and expressing Stella at E7.25 are also specified.[15][16] In between E7.5 and E12.5, these PGCs migrate towards thegenital ridge, where they form thetesticular cords, via thecytokine interactions of theCXCR4 andc-Kit membrane receptors and their ligandsSDF1 and SCF respectively.[17][18][19] During this migratory period, PGCs undergoepigenetic reprogramming throughgenome-wideDNA demethylation.[18] Once resident in the genital ridge, these germ cells and surrounding supporting cells undergosex determination driven by the expression of theSRY gene.[20] It is only after these developmental steps that the germ cells present in the developed testicular cords are identified as gonocytes.[3]
In order to provide the long-term production of sperm, gonocytes undergo proliferation to produce a populate pool of SSCs.[3][12][4] Once enclosed bySertoli cells to form the testicular cords, gonocytes undergo a succession of differing fetal and neonatal periods of mitosis, with a phase of quiescence in between.[1] 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.[1][3] As many populations of gonocytes are in different stages of development, mitotic and quiescent gonocytes coexist in neonatal developingtestes.[6]
Proliferation in fetal and neonatal gonocytes is differently regulated.Retinoic acid (RA), thebioactivemetabolite ofretinal, is amorphogen shown to modulate fetal gonocyte proliferation. Investigation of fetal gonocyte activity inorgan cultures recorded RA to slightly stimulate proliferation.[21][22] 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 ofmutated and dysfunctional germ cells.[22] The activation ofprotein kinase C byphorbol ester PMA also decreased fetal gonocyte mitotic activity.[23]
There are a number of factors that influence neonatal gonocyte proliferation, including17β‐estradiol (E2),Leukemia inhibitory factor (LIF),platelet-derived growth factor (PDGF)-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.[24][25] 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.[26] 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.[3][21][22]
The migration of gonocytes to the basement membrane of the seminiferous cords is necessary for their differentiation into SSCs.[1][12][4] 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.[27] Although c-Kit expression is evident in a small fraction of neonatal gonocytes,[28] they also express ofPDGF receptor beta (PDGFRβ) on their membrane to aid in their migration.[29] Inhibition of PDGF receptors and c-Kit byin vivo treatment ofimatinib, an inhibitorydrug, interrupted migration, leading to a number of gonocytes centrally located in the seminiferous cords.[24]
TheADAM-Integrin-Tetraspanin complexes, which is a family ofproteins, 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 wherespermatogonia normally reside, allowing the gonocyte to migrate and bind to the basement membrane.[30]
The differentiation of gonocytes to SSC only occur once the cells have established close contact with the basement membrane in the seminiferous cords.[3][12] RA is the best characterised activator of gonocyte differentiation.[3]De novo synthesis of RA involvesretinol, the precursor to RA, being transported to the membrane receptorSTRA6 by theretinol-binding protein released by Sertoli cells. Binding of retinol to STRA6endocytoses retinol into the cell, whereby it undergoesoxidation reactions to form RA. RA is also directly transported from the surrounding Sertoli cells or thevasculature. RA internalization triggers a variety of pathways that modulate the differentiation, such as PDGF receptorpathways andJanus kinase 2 (JAK2) signaling pathway.[22]
Anti-Müllerian hormone (AMH), aglycoproteingonadal hormone produced by Sertoli cells in early development, is the onlyhormone to significantly increase the number of successfully differentiated gonocytes.[31]
The timing of differentiation is regulated byNOTCH signaling.[32] The functional components of the NOTCH signaling pathway are expressed and released by both developing and adult Sertoli cells.[33] 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.[32][33]
Gonocytes are large cells with a sphericaleuchromaticnucleus, twonucleoli and a surrounding, ring-likecytosol.[6][34] 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.[6][35][3] Gonocytes are attached to Sertoli cells bygap junctions,[35]desmosome junctions[3] and a number of different cell adhesion molecules such asconnexin 43,PB-cadherin andNCAM[6] for regulation ofcell-to-cell communication.[35][3] 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 undergophenotypic changes and take the appearance of spermatogonia.[6][3]
Dysfunctional development in germ cells plays a significant role in fertility-relateddiseases.[3][4] The development of PGCs to gonocytes, and gonocyte differentiation to SSCs is critical for adultfertility and the defective growth often leads toinfertility.[3]
Testicular germ cell tumors, that occur primarily in young adults, are the consequent of preinvasive cells calledcarcinoma in situ (CIS).[36] The development of CIS is due to fetal germ cells, such as gonocytes, arrested in quiescence and unable to properly differentiate.[36][37] This leads tomalignant transformation of the germ cells until it becomes an overt germ cellcancer afterpuberty.[37]
Cryptorchidism, also known as undescended testis, is a commonbirth defect affectingmale genital formation.[38] Individuals diagnosed with cryptorchidism are often at risk oftesticular 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.[4] It is proposed that this dysfunction is a product of heat stress caused by the undescended testes remaining in theabdomen and unable to regulate its temperature which is often accomplished by thescrotum.[39]
{{cite journal}}: CS1 maint: multiple names: authors list (link){{cite journal}}: CS1 maint: multiple names: authors list (link)