Gonocyte

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Gonocytes are the precursors of spermatogonia that differentiate in the testis from primordial germ cells around week 7 of embryonic development and exist up until the postnatal period, when they become spermatogonia. [1] Despite some uses of the term to refer to the precursors of oogonia, it was generally restricted to male germ cells. [1] [2] 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). [3]

Contents

Gonocytes represent the germ cells undergoing the successive, short-term and migratory stages of development. This occurs between the time they inhabit the forming gonads on the genital ridge to the time they migrate to the basement membrane of the seminiferous cords. Gonocyte development consists of several phases of cell proliferation, differentiation, migration and apoptosis. [4] [5] The abnormal development of gonocytes leads to fertility-related diseases. [6]

They are also identified as prespermatogonia, prospermatogonia and primitive germ cells, although gonocyte is most common. [7]

History

Gonocytes are described as large and spherical, with a prominent nucleus and two nucleoli. [1] The term, gonocyte, was created in 1957 by Canadian scientists Yves Clermont and Bernard Perey. [2] They considered it essential to study the origin of spermatogonia and carried out a study on rats to investigate this. [8] In 1987, Clermont referred to gonocytes as the cells that differentiate into type A spermatogonia, which differentiate into type B spermatogonia and spermatocytes. [2]

Very few studies used gonocytes to also refer to the female germ cells in the ovarium primordium. [9] 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. [7] [9]

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. [2] A 2006 study found that some gonocytes differentiate straight into committed spermatogonia (type B) rather than spermatogonial stem cells (type A). [1]

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. [10] 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. [11] Gonocytes migrate to the basement membrane to proliferate. Gonocytes that do not migrate undergo apoptosis and are cleared from the seminiferous epithelium. [12] Spermatogonia are formed in infancy and differentiate throughout adult life. [13]

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. [3]

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, which is a cycle of regulated mitosis, meiosis and differentiation (via spermiogenesis) leading to the production of mature spermatozoa, also known as sperm cells. [4] [14] [15]

Gonocytes are functionally present during the first phase of germ cell maturation and development. [5] [14] This period consists of the primordial germ cells (PGC), the initial cells that commence germ cell development in the embryo, [16] and the gonocytes, which after being differentiated from PGCs, undergo regulated proliferation, differentiation, migration and apoptosis to produce the SSCs. [4] [5] Gonocytes therefore correspond to the developmental stages between the PGCs and SSCs.

Formation

Gonocytes are formed from the differentiation of PGCs. [5] Embryonic cells initiate germ cell development in the proximal epiblast located near the extra-embryonic ectoderm by the release of bone morphogenetic protein 4 (BMP4) and BMP8b. These proteins specify embryonic cells into PGCs expressing the genes PRDM1 and PRDM14 at embryonic day (E) 6.25. The PGCs which are positively stained by alkaline phosphatase and expressing Stella at E7.25 are also specified. [17] [18] In between E7.5 and E12.5, these PGCs migrate towards the genital ridge, where they form the testicular cords, via the cytokine interactions of the CXCR4 and c-Kit membrane receptors and their ligands SDF1 and SCF respectively. [19] [20] [21] During this migratory period, PGCs undergo epigenetic reprogramming through genome-wide DNA demethylation. [20] Once resident in the genital ridge, these germ cells and surrounding supporting cells undergo sex determination driven by the expression of the SRY gene. [22] It is only after these developmental steps that the germ cells present in the developed testicular cords are identified as gonocytes. [5]

Proliferation

In order to provide the long-term production of sperm, gonocytes undergo proliferation to produce a populate pool of SSCs. [5] [14] [6] Once enclosed by Sertoli 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. [4] 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. [4] [5] As many populations of gonocytes are in different stages of development, mitotic and quiescent gonocytes coexist in neonatal developing testes. [9]

Proliferation in fetal and neonatal gonocytes is differently regulated. Retinoic acid (RA), the bioactive metabolite of retinal, is a morphogen shown to modulate fetal gonocyte proliferation. Investigation of fetal gonocyte activity in organ cultures recorded RA to slightly stimulate proliferation. [23] [24] 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 and dysfunctional germ cells. [24] The activation of protein kinase C by phorbol ester PMA also decreased fetal gonocyte mitotic activity. [25]

There are a number of factors that influence neonatal gonocyte proliferation, including 17β‐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. [26] [27] 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. [28] 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. [5] [23] [24]

Migration

The migration of gonocytes to the basement membrane of the seminiferous cords is necessary for their differentiation into SSCs. [4] [14] [6] 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. [29] Although c-Kit expression is evident in a small fraction of neonatal gonocytes, [30] they also express of PDGF receptor beta (PDGFRβ) on their membrane to aid in their migration. [31] Inhibition of PDGF receptors and c-Kit by in vivo treatment of imatinib, an inhibitory drug, interrupted migration, leading to a number of gonocytes centrally located in the seminiferous cords. [26]

The ADAM-Integrin-Tetraspanin complexes, which is a family of proteins, 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 normally reside, allowing the gonocyte to migrate and bind to the basement membrane. [32]

Differentiation

Oxidation reactions required for retinol to become retinoic acid in the gonocyte cell Retinoic Acid synthesis.png
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. [5] [14] RA is the best characterised activator of gonocyte differentiation. [5] De novo synthesis of RA involves retinol, the precursor to RA, being transported to the membrane receptor STRA6 by the retinol-binding protein released by Sertoli cells. Binding of retinol to STRA6 endocytoses retinol into the cell, whereby it undergoes oxidation reactions to form RA. RA is also directly transported from the surrounding Sertoli cells or the vasculature. RA internalization triggers a variety of pathways that modulate the differentiation, such as PDGF receptor pathways and Janus kinase 2 (JAK2) signaling pathway. [24]

Anti-Müllerian hormone (AMH), a glycoprotein gonadal hormone produced by Sertoli cells in early development, is the only hormone to significantly increase the number of successfully differentiated gonocytes. [33]

The timing of differentiation is regulated by NOTCH signaling. [34] The functional components of the NOTCH signaling pathway are expressed and released by both developing and adult Sertoli cells. [35] 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. [34] [35]

Structure of Gonocytes

Gonocytes are large cells with a spherical euchromatic nucleus, two nucleoli and a surrounding, ring-like cytosol. [9] [36] 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. [9] [37] [5] Gonocytes are attached to Sertoli cells by gap junctions, [37] desmosome junctions [5] and a number of different cell adhesion molecules such as connexin 43, PB-cadherin and NCAM [9] for regulation of cell-to-cell communication. [37] [5] 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 changes and take the appearance of spermatogonia. [9] [5]

Diseases

Dysfunctional development in germ cells plays a significant role in fertility-related diseases. [5] [6] The development of PGCs to gonocytes, and gonocyte differentiation to SSCs is critical for adult fertility and the defective growth often leads to infertility. [5]

Testicular cancer

Testicular germ cell tumors, that occur primarily in young adults, are the consequent of preinvasive cells called carcinoma in situ (CIS). [38] The development of CIS is due to fetal germ cells, such as gonocytes, arrested in quiescence and unable to properly differentiate. [38] [39] This leads to malignant transformation of the germ cells until it becomes an overt germ cell cancer after puberty. [39]

Cryptorchidism

Cryptorchidism, also known as undescended testis, is a common birth defect affecting male genital formation. [40] Individuals diagnosed with cryptorchidism are often at risk of 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. [6] It is proposed that this dysfunction is a product of heat stress caused by the undescended testes remaining in the abdomen and unable to regulate its temperature which is often accomplished by the scrotum. [41]

Related Research Articles

<span class="mw-page-title-main">Androgen</span> Any steroid hormone that promotes male characteristics

An androgen is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes the embryological development of the primary male sex organs, and the development of male secondary sex characteristics at puberty. Androgens are synthesized in the testes, the ovaries, and the adrenal glands.

<span class="mw-page-title-main">Germ cell</span> Gamete-producing cell

A germ cell is any cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they undergo meiosis, followed by cellular differentiation into mature gametes, either eggs or sperm. Unlike animals, plants do not have germ cells designated in early development. Instead, germ cells can arise from somatic cells in the adult, such as the floral meristem of flowering plants.

<span class="mw-page-title-main">Cryptorchidism</span> Medical condition

Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek κρυπτός 'hidden' and ὄρχις 'testicle'. It is the most common birth defect of the male genital tract. About 3% of full-term and 30% of premature infant boys are born with at least one undescended testis. However, about 80% of cryptorchid testes descend by the first year of life, making the true incidence of cryptorchidism around 1% overall. Cryptorchidism may develop after infancy, sometimes as late as young adulthood, but that is exceptional.

<span class="mw-page-title-main">Leydig cell</span> Androgen-producing cell adjacent to the seminiferous tubules of the testicle

Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral in shape and have a large, prominent nucleus, an eosinophilic cytoplasm, and numerous lipid-filled vesicles.

<span class="mw-page-title-main">Spermatogenesis</span> Production of sperm

Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testicle. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubules. These cells are called spermatogonial stem cells. The mitotic division of these produces two types of cells. Type A cells replenish the stem cells, and type B cells differentiate into primary spermatocytes. The primary spermatocyte divides meiotically into two secondary spermatocytes; each secondary spermatocyte divides into two equal haploid spermatids by Meiosis II. The spermatids are transformed into spermatozoa (sperm) by the process of spermiogenesis. These develop into mature spermatozoa, also known as sperm cells. Thus, the primary spermatocyte gives rise to two cells, the secondary spermatocytes, and the two secondary spermatocytes by their subdivision produce four spermatozoa and four haploid cells.

<span class="mw-page-title-main">Sertoli cell</span> Cells found in human testes which help produce sperm

Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of spermatogenesis as a structural component of the seminiferous tubules. They are activated by follicle-stimulating hormone (FSH) secreted by the adenohypophysis and express FSH receptor on their membranes.

<span class="mw-page-title-main">Spermatocyte</span> Sperm precursor cell that undergoes meiosis

Spermatocytes are a type of male gametocyte in animals. They derive from immature germ cells called spermatogonia. They are found in the testis, in a structure known as the seminiferous tubules. There are two types of spermatocytes, primary and secondary spermatocytes. Primary and secondary spermatocytes are formed through the process of spermatocytogenesis.

<span class="mw-page-title-main">Male reproductive system</span> Reproductive system of the human male

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<span class="mw-page-title-main">Spermatogonium</span> Undifferentiated male germ cell

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<span class="mw-page-title-main">Sex cords</span> Structures that develop from the genital ridges that further differentiate based on an embryos sex

Sex cords are embryonic structures which eventually will give rise (differentiate) to the adult gonads. They are formed from the genital ridges - which will develop into the gonads - in the first 2 months of gestation which depending on the sex of the embryo will give rise to male or female sex cords. These epithelial cells penetrate and invade the underlying mesenchyme to form the primitive sex cords. This occurs shortly before and during the arrival of the primordial germ cells (PGCs) to the paired genital ridges. If there is a Y chromosome present, testicular cords will develop via the Sry gene : repressing the female sex cord genes and activating the male. If there is no Y chromosome present the opposite will occur, developing ovarian cords. Prior to giving rise to sex cords, both XX and XY embryos have Müllerian ducts and Wolffian ducts. One of these structures will be repressed to induce the other to further differentiate into the external genitalia.

<span class="mw-page-title-main">Adjudin</span> Chemical compound

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

Stem-cell niche refers to a microenvironment, within the specific anatomic location where stem cells are found, which interacts with stem cells to regulate cell fate. The word 'niche' can be in reference to the in vivo or in vitro stem-cell microenvironment. During embryonic development, various niche factors act on embryonic stem cells to alter gene expression, and induce their proliferation or differentiation for the development of the fetus. Within the human body, stem-cell niches maintain adult stem cells in a quiescent state, but after tissue injury, the surrounding micro-environment actively signals to stem cells to promote either self-renewal or differentiation to form new tissues. Several factors are important to regulate stem-cell characteristics within the niche: cell–cell interactions between stem cells, as well as interactions between stem cells and neighbouring differentiated cells, interactions between stem cells and adhesion molecules, extracellular matrix components, the oxygen tension, growth factors, cytokines, and the physicochemical nature of the environment including the pH, ionic strength and metabolites, like ATP, are also important. The stem cells and niche may induce each other during development and reciprocally signal to maintain each other during adulthood.

The development of the gonads is part of the prenatal development of the reproductive system and ultimately forms the testicles in males and the ovaries in females. The immature ova originate from cells from the dorsal endoderm of the yolk sac. Once they have reached the gonadal ridge they are called oogonia. Development proceeds and the oogonia become fully surrounded by a layer of connective tissue cells. In this way, the rudiments of the ovarian follicles are formed.

<span class="mw-page-title-main">Sertoli cell-only syndrome</span> Medical condition

Sertoli cell-only syndrome (SCOS), also known as germ cell aplasia, is defined by azoospermia where the testicular seminiferous tubules are lined solely with sertoli cells. Sertoli cells contribute to the formation of the blood-testis barrier and aid in sperm generation. These cells respond to follicle-stimulating hormone, which is secreted by the hypothalamus and aids in spermatogenesis.

Testicular Immunology is the study of the immune system within the testis. It includes an investigation of the effects of infection, inflammation and immune factors on testicular function. Two unique characteristics of testicular immunology are evident: (1) the testis is described as an immunologically privileged site, where suppression of immune responses occurs; and, (2) some factors which normally lead to inflammation are present at high levels in the testis, where they regulate the development of sperm instead of promoting inflammation.

<span class="mw-page-title-main">Spermatogonial stem cell</span> Spermatogonium that does not differentiate into a spermatocyte

A spermatogonial stem cell (SSC), also known as a type A spermatogonium, is a spermatogonium that does not differentiate into a spermatocyte, a precursor of sperm cells. Instead, they continue dividing into other spermatogonia or remain dormant to maintain a reserve of spermatogonia. Type B spermatogonia, on the other hand, differentiate into spermatocytes, which in turn undergo meiosis to eventually form mature sperm cells.

<span class="mw-page-title-main">Peritubular myoid cell</span> Smooth muscle cell found in testis

A peritubular myoid (PTM) cell is one of the smooth muscle cells which surround the seminiferous tubules in the testis. These cells are present in all mammals but their organization and abundance varies between species. The exact role of PTM cells is still somewhat uncertain and further work into this is needed. However, a number of functions of these cells have been established. They are contractile cells which contain actin filaments and are primarily involved in transport of spermatozoa through the tubules. They provide structural integrity to the tubules through their involvement in laying down the basement membrane. This has also been shown to affect Sertoli cell function and PTM cells also communicate with Sertoli cells through the secretion of growth factors and ECM components. Studies have shown PTM cells to be critical in achieving normal spermatogenesis. Overall, PTM cells have a role in both maintaining the structure of the tubules and regulating spermatogenesis through cellular interaction.

In vitro spermatogenesis is the process of creating male gametes (spermatozoa) outside of the body in a culture system. The process could be useful for fertility preservation, infertility treatment and may further develop the understanding of spermatogenesis at the cellular and molecular level. 

The germ cell nest forms in the ovaries during their development. The nest consists of multiple interconnected oogonia formed by incomplete cell division. The interconnected oogonia are surrounded by somatic cells called granulosa cells. Later on in development, the germ cell nests break down through invasion of granulosa cells. The result is individual oogonia surrounded by a single layer of granulosa cells. There is also a comparative germ cell nest structure in the developing spermatogonia, with interconnected intracellular cytoplasmic bridges.

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  30. ↑ Prabhu, Sridurga Meistrich, Marvin McLaughlin, Eileen Roman, Shaun Warne, Sam Mendis, Sirisha Itman, Catherine Loveland, Kate (2006). "Expression of c-Kit receptor mRNA and protein in the developing, adult and irradiated rodent testis". Reproduction. 131 (3). Bio Scientifica Ltd: 489–99. doi: 10.1530/rep.1.00968 . OCLC   696515509. PMID   16514192.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ↑ Wang, Yan; Culty, Martine (2007-05-01). "Identification and Distribution of a Novel Platelet-Derived Growth Factor Receptor β Variant: Effect of Retinoic Acid and Involvement in Cell Differentiation". Endocrinology. 148 (5): 2233–2250. doi: 10.1210/en.2006-1206 . ISSN   0013-7227. PMID   17303670.
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  35. 1 2 Garcia, Thomas Xavier; DeFalco, Tony; Capel, Blanche; Hofmann, Marie-Claude (2013). "Constitutive activation of NOTCH1 signaling in Sertoli cells causes gonocyte exit from quiescence". Developmental Biology. 377 (1): 188–201. doi:10.1016/j.ydbio.2013.01.031. ISSN   0012-1606. PMC   3630254 . PMID   23391689.
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