The adult Leydig cell precursors are hypothesized to derive from adult stem Leydig cells Ge et al. Pdgfra and kit expression is high in progenitor Leydig cells, but decreases as these progenitor cells transition to adult Leydig cells Ge et al. Dhh and Pdgfa expression by Sertoli cells are again involved in paracrine signaling during adult Leydig cell development, based on the observation that targeted deletion of these genes prevent the establishment of adult Leydig cells Clark et al.
Thus, Sertoli cells again appear to modulate Leydig cell function Mariani et al. Another signaling pathway that could contribute to the development of adult Leydig cells involves KIT ligand and its receptor Table 2. KIT ligand, on the other hand, is produced by stem Leydig cells Ge et al. KIT ligand induces proliferation and survival of germ cells, so a similar role for this factor could be hypothesized for the Leydig cell lineage. Indeed, an antibody directed against KIT receptor can partially block the regeneration of Leydig cells in rats previously treated with ethane dimethane sulphonate, which destroys the cell population of the interstitial compartment Yan et al.
Two additional signaling systems not heavily utilized in the fetal testis may contribute to adult Leydig cell differentiation. Nerve growth factor NGF has also been shown to promote proliferation of stem, progenitor, and immature Leydig cells as well as induce the expression of steroidogenic enzymes in vitro Zhang et al. Unfortunately, constitutive mutations of these ligands or their respective receptors are perinatal lethal, making investigation of phenotypic alterations to male reproduction difficult.
Although LH stimulation is required for adult Leydig cell development, it does not seem to be required for the initial differentiation of stem into progenitor Leydig cells; indeed, progenitor Leydig cells express an inactive form of LHCGR Shan and Hardy, Androgens from the adrenal glands are also required for the differentiation of adult Leydig cell precursors Hardy et al. Furthermore, postnatal Leydig cells may produce androgens that provide autocrine regulation Shan et al. Testicular androgens further exert paracrine activity via Sertoli cell AR, which is essential for the functional differentiation of Sertoli cells and, in turn, provides reciprocal control for postnatal completion of adult Leydig cell development De Gendt et al.
The role of NR5A1 in the development and differentiation of adult Leydig cells remains a puzzle—despite its undeniable role in regulating steroidogenesis. For example, conditional disruption of Nr5a1 in Leydig cells reduced, but did not entirely prevent, their differentiation Jeyasuria et al. This result implied that other transcription factors may be involved in adult Leydig cell development, including the orphan nuclear receptor Nr4a1 , which is highly expressed during progenitor Leydig cell development Song et al. NR2F2 is expressed in peritubular myoid cells and in stem Leydig cells Qin et al.
Indeed, inducible inactivation of NR2F2 in prepubertal male mice prevented the development of adult Leydig cells Qin et al. Once differentiated, adult Leydig cells primarily participate in two important processes that support spermatogenesis: testosterone production and the synthesis and secretion of INSL3. Different transcription factors participate in this process, including NR5A1 Bakke et al. INSL3 is regulated very differently from testosterone, although its expression is also acutely sensitive to LH Bay et al.
INSL3 synthesis and steroidogenesis therefore appear to be uncoupled in fully differentiated adult Leydig cells. Like testosterone Salameh et al. Yet, during the spontaneous recovery period, INSL3 production fails to improve to the same extent as testosterone Bay et al. Thus, the characteristics of INSL3 expression render it an excellent marker of Leydig cell differentiation and function Ivell et al.
Current findings on gene and hormonal regulation of fetal and adult Leydig cell differentiation highlights the complex interplay among the signaling pathways involved. Expression of Dhh and Ptch1 as well as Pdgfa and Pdgfra emerge as critical for both fetal and adult Leydig cell differentiation Tables 1 and 2. Although more than 30 years of research have contributed to our understanding of the molecular mechanisms responsible for the generation of both Leydig cell populations, several critical questions remain to be clarified: What are the origins of fetal and adult Leydig cell lineages?
When do the precursors of adult Leydig cells appear within the testis? Are other homeoproteins and nuclear receptors critical for the differentiation of the adult Leydig cell population? And, what are the roles of different interstitial cell types on the differentiation of Leydig cells? Volume 83 , Issue 6.
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Share Give access Share full text access. Share full text access. Please review our Terms and Conditions of Use and check box below to share full-text version of article. SUMMARY Leydig cells, located within the interstitial compartment of the testis, are major contributors of androgen synthesis and secretion, which play an important role in testis development, normal masculinization, maintenance of spermatogenesis, and general male fertility.
Figure 1 Open in figure viewer PowerPoint. Macrophages A population of cells in the interstitium of the testis of newborn rats possess specific markers of monocytes and macrophages, and expands in number and size as the cells differentiate Raburn et al. Peritubular Myoid Cells Seminiferous tubules are surrounded by peritubular myoid cells, a population of contractile smooth muscle cells that are organized in multiple layers around seminiferous tubules in humans. Endothelial Cells and Others Less is known about the contribution of interstitial fibroblasts, lymphocytes, pericytes, and vascular and lymphatic endothelial cells—all relatively abundant within the testicular interstitium—towards Leydig cell function, development, and differentiation.
Figure 2 Open in figure viewer PowerPoint. Testicular Leydig cell development and differentiation. Under the influence of different factors, these fetal stem Leydig cells proliferate and differentiate into fetal Leydig cells expressing steroidgenic genes required for androgen production.
The major androgens produced by fetal Leydig cells are androstenedione in rodents and testosterone, in response to hCG, in humans. Progenitor Leydig cells undergo several cycles of cell proliferation, as stimulated by paracrine factors as well as hormones, such as triiodothyronine T3 , prolactin PRL , and LH reviewed by Teerds and Huhtaniemi, The major androgens produced by progenitor Leydig cells are androsterone and androstenedione.
Under the influence of LH, progenitor Leydig cells differentiate into immature Leydig cells, undergoing one more cycle of proliferation before differentiation into mature adult Leydig cells. Testosterone becomes the major androgen produced by adult Leydig cells. The adult Leydig cell population is also relatively stable, but may become proliferative under special circumstances. Expression of critical steroidogenic genes is presented according to the fetal versus adult phase of development in rodents. Human Neonatal Leydig Cells A neonatal Leydig cell population develops and differentiates in humans, peaking around 2—4 months after birth Codesal et al.
Longitudinal reproductive hormone profiles in infants: Peak of inhibin B levels in infant boys exceeds levels in adult men. J Clin Endocrinol Metab 83 : — Google Scholar. Citing Literature. Volume 83 , Issue 6 June Pages Figures References Related Information. Close Figure Viewer. Browse All Figures Return to Figure. Previous Figure Next Figure. The intercellular bridge is considered to be the first visible sign of spermatogonial differentiation Aponte et al.
The ratio of self-renewal and differentiation must be strictly maintained around , otherwise germ cell tumors or depletion of SSCs may occur when the balance skews either way Meng et al. At this point, the molecular mechanism underlying this decision toward incomplete cytokinesis and differentiation is largely unknown. The arrows shows the intercellular bridge connecting two Intermediate spermatogonia.
In a recent study, Greenbaum and colleagues reported that testis-expressed gene 14 TEX14 is an essential component of germ cell intercellular bridges and the intercellular bridges could not be observed by electron microscopy among the Tex14 -null spermatogonia. The proliferation and differentiation of Tex14 -null spermatogonia appeared to be unaffected but spermatogenesis was halted before the completion of the first meiotic division Greenbaum et al. During each cycle of the seminiferous epithelium, most of the A al spermatogonia differentiate into A 1 spermatogonia at about stage VII De Rooij, Most of the known factors regulating spermatogonial differentiation are active in the transition of cells from A al to B spermatogonia.
A summary of the actions of these regulatory factors follows. RA, a biologically active metabolite of vitamin A retinol , is essential for male fertility Griswold et al. At 24—48 hours after the injection of either retinol or RA, arrested A al spermatogonia re-entered the cell cycle and differentiate into A 1 spermatogonia with the subsequent increased expression of kit oncogene Kit in type A spermatogonia Schrans-Stassen et al. In long-term experiments with VAD mice or rats after the replacement of retinol or RA, several rounds of synchronous spermatogenesis occurred van Pelt and de Rooij, ; Griswold et al.
It is difficult to determine whether RA induction of spermatogonial differentiation is a direct action in germ cells or an indirect regulation via Sertoli cells, since receptors for retinoids are expressed in both somatic and germ cells Dufour and Kim, Recent studies show a robust induction by RA of a gene named Stra8 , together with Kit , in the cultured A undiff spermatogonia without the presence of somatic cells Zhou et al. This result suggests that RA regulation of differentiation is a direct action on spermatogonia. RA is a general differentiating factor for many cells and tissues at multiple developmental stages Clagett-Dame and DeLuca, There is some evidence that RA interacts with several other factors involved in the regulation of spermatogonial differentiation.
Secondly, RA induced spermatogonial differentiation in cultured cryptorchid testes Haneji et al. More importantly, expression of Stra8 was significantly up-regulated in cryptorchid testes 24 hours after the injection of RA to these animals unpublished data. Thirdly, the level of deleted in azoospermia-like Dazl was significantly up-regulated by RA treatment in VAD mouse testes unpublished data.
Finally, RA treatment dramatically down-regulates genes coding for two key enzymes involved in testosterone production, cytochrome P, family 17, subfamily a, polypeptide 1 Cyp17a1 and cytochrome P, family 11, subfamily a, polypeptide 1 Cyp11a1 , in VAD mice testes unpublished data. If this inhibition of Cyp17a1 and Cyp11a1 by RA can be translated to a regulation of testosterone synthesis under physiological conditions, it suggests that RA and testosterone have reciprocal actions in the testis. De Rooij et al. The most advanced germ cells present in Sl17h seminiferous tubules were actively proliferating A undiff spermatogonia revealed by their topological arrangement and clonal sizes.
These cells failed to differentiate into A 1 spermatogonia. Accumulation of A al spermatogonia was not observed due to the apoptosis in spermatogonia de Rooij et al. Dazl encodes an RNA-binding protein essential for both male and female fertility Ruggiu et al. A genetic defect, microdeletions of the long arm of the Y-chromosome, is the cause of some cases of human oligozoospermia or azoospermia deKretser, One of the human Y-chromosome genes identified within this region is deleted in azoospermia Daz Ruggiu and Cooke, However, Daz only exists in the human and some primates.
In other mammals, it is represented by a single-copy, autosomal gene Dazl Cooke et al. Dazl -null murine seminiferous tubules contained spermatogonia with very few tubules containing pachytene spermatocytes. The clonal composition study using tubule whole mounts indicated that the spermatogonia that remained in the null tubules were A undiff spermatogonia Schrans-Stassen et al.
BrdU incorporation and the mitotic index of cells in the null testes showed that these A undiff spermatogonia were actively proliferating but were also undergoing active apoptosis. The SRY -box containing gene 3 Sox3 is a single-exon gene located on the X-chromosome, that belongs to a family of the high mobility group HMG of transcription factors Foster and Graves, Testicular defects became evident in 10 dpp null testes as type A spermatogonia were the only germ cells present within the seminiferous tubules.
Proliferation of the germ cells seemed normal and TUNEL assay performed at 1, 2 and 3 weeks of age did not detect any significant differences in apoptosis between WT and null testes. However, it was found that mRNA and protein expression of Neurog3 was reduced, whereas the Pou5f1 mRNA level was increased and Ret level remained the same in null testes.
Collectively, these data suggest that there is an inability of Sox3 -null A undiff spermatogonia to differentiate and the regulation of differentiation by Sox3 may involve NEUROG3 Raverot et al. Spermatogenesis and oogenesis specific basic helix-loop-helix 1 SOHLH1 is a transcription factor preferentially expressed in type A spermatogonia Ballow et al.
Sohlh1 -null males are sterile. TUNEL assays revealed the greatest difference in apoptosis between wild types and nulls occurred at 15 dpp Ballow et al. This appeared to be due to dying spermatocytes, and the apoptotic index declined with age due to reduced numbers of spermatocytes observed in the tubules of older animals.
The mitotic index revealed by BrdU incorporation in Sohlh1 -null spermatogonia was very close to that of juvenile spermatogonial depletion Jsd mice.
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A few spermatocytes were observed in a low percentage of the seminiferous tubules of prepubertal Sohlh1 -null testes. However, the exact step of spermatogonial differentiation in which this block occurred was uncertain. Spermatogenesis and oogenesis specific basic helix-loop-helix 1 SOHLH2 is a germ cell specific transcription factor Ballow et al.
Male Sohlh2 -null mice were infertile Hao et al. Postnatal Sohlh2 -null mice had reduced numbers of intermediate and type-B spermatogonia, seemingly normal undifferentiated spermatogonia and degenerating colonies of differentiating spermatogonia. Degenerating cells resembled A 2 spermatogonia, and accumulated in M-phase prior to death.
In mice that are homozygous for the Jsd mutation, a single wave of spermatogenesis is followed by failure of type A spermatogonia to differentiate, rendering male animals sterile, whereas female animals are apparently normal Boettger-Tong et al. Hormonal profiles of Jsd homozygous males indicated that the circulating testosterone level was normal and the serum FSH level was elevated in young animals but returned to normal at 1 year of age.
Germ cell transplantation studies showed spermatogenic failure in Jsd was due to a defect in germ cells but not in the intra-tubular somatic environment Boettger-Tong et al. De Rooij and his colleagues reported spermatogenic phenotypes in adult Jsd mutant testes resembled what is observed in Sl17h mutants, including actively proliferating A undiff spermatogonia accompanied by spermatogonial apoptosis de Rooij et al.
Occasionally, a few B spermatogonia were observed in Jsd adult seminiferous tubules. Recent studies identified a small rearrangement within a gene named UTP14, U3 small nucleolar ribonucleoprotein, homolog B yeast Utp14b underlying the Jsd phenotype. Utp14b represents a testis-specific retroposed copy of the ubiquitously expressed X-linked gene Utp14a Rohozinski and Bishop, ; Bradley et al. Because yeast Utp14 , the homologue of mouse Utp14a , is an essential component of a large ribonucleoprotein complex containing the U3 small nucleolar RNA, Rohozinski and Bishop proposed the autosomal retroposon Upt14b has been selected for in evolution due to its stability to increase the efficiency of protein production during spermatogenesis Rohozinski and Bishop, Bradley et al proposed that it may imply a strong selective pressure to enable ribosome assembly in male meiotic cells Bradley et al.
The rate and severity of spermatogonial depletion in mice with different genetic backgrounds were studied and it was concluded that the source of Y-chromosome was a major factor in determining the severity of spermatogonial depletion in Utp14b jsd mutant mice Bolden-Tiller et al. Testosterone has no direct impact on germ cell development but indirectly regulates spermatogenesis through Sertoli cells Johnston et al.
A deficiency in testosterone production or defects in androgen receptor results in a halt of spermatogenesis in the middle of meiosis, indicating testosterone action in Sertoli cells is essential for the completion of meiosis in males Holdcraft and Braun, a. Numerous studies also showed testosterone was required for spermiogenesis and spermiation Holdcraft and Braun, b. There is no current evidence to suggest spermatogonial differentiation and self-renewal requires the presence of testosterone.
On the contrary, the presence of a normal testosterone level is suggested to be inhibitory to spermatogonial differentiation in three different animal models, including irradiated rats Shetty et al. It seems that the beneficial effects of testosterone are exhibited in mid-meiosis and later stages of spermatogenesis, while the detrimental effects reside in differentiating spermatogonia.
It is also worth noting that the destructive role of testosterone can be only observed either under the pathological condition or in naturally mutated rodents. We speculate that a delicate fine-tuning of focal testosterone action during the seminiferous epithelial cycle in normal testis is essential to coordinate the regulatory requirements for a successful spermatogenesis. Cryptorchidism, where testes fail to descend into the scrotum and reside in an environment of body temperature, results in a spermatogenic arrest and infertility. The severity of this arrest highly correlates to the genetic backgrounds of the mice being studied.
The nature and cellular activity of these A undiff spermatogonia resemble what was observed in Sl17h and Jsd homologous mutant testes de Rooij et al. Cryptorchid testes showed many similarities with those from Jsd mice as both models contained seminiferous tubules with A undiff spermatogonia but with few B spermatogonia.
For instance, artificial cryptorchidism generated by surgery rescued the spermatogonial arrest observed in Jsd mutants Shetty and Weng, Moreover, additional studies are required to understand why normal testosterone levels and scrotum temperatures are destructive to spermatogonial differentiation when Utp14b is mutated. Stimulated by retinoic acid gene 8 Stra8 was first identified as a gene under RA regulation in several carcinoma cell lines OuladAbdelghani et al. Recent studies showed it is a required down-stream mediator of RA action on initiation of meiosis in both male and female germ cells Koubova et al.
Stra8 -null animals were sterile in both males and females Baltus et al. Spermatogenesis was halted in Stra8 -nulls around preleptotene spermatocytes Baltus et al. It was also demonstrated that Stra8 induced by RA was closely correlated to spermatogonial differentiation and proliferation in vitro and in vivo Zhou et al. Whether Stra8 is required for the differentiation process and the exact mechanism of Stra8 regulation in spermatogonia is yet to be determined.
The NANOS3 protein is expressed in both male and female gonads of early embryo and, after birth, is expressed only in A undiff spermatogonia. Up-regulation of Nanos3 caused the accumulation of the cells in the G 1 phase and treatment of A undiff spermatogonia with retinoic acid RA resulted in a dramatic down-regulation of Nanos3. Nanos3 targeted disruption resulted in the complete loss of germ cells in both sexes. Future studies are needed to define the function of NANOS3 in the self-renewal and differentiation of spermatogonia Lolicato et al.
Phenotype analyses and mechanistic studies using genetic models have resulted in several major advances in our understanding of spermatogonial self-renewal and differentiation. The summary depicted in Figure 2 represents the present knowledge about the regulation of spermatogonia. It is important to note that many genetically modified mice with spermatogenic failure have yet to be studied in enough detail to fully understand the mechanisms of regulation.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Skip to main content. You are here Home. Spermatogenesis: in general Spermatogenesis is a complex process, in which spermatogonial stem cells form spermatozoa. Figure 1. Spermatogonia In rodents, spermatogonial stem cells SSCs are single cells located on the basement membrane of the seminiferous tubules.
Table 1. Overview of the genes essential for the regulation of mitotic phase of spermatogenesis. Figure 2. Scheme of spermatogonial self-renewal and differentiation in the mouse, showing the subsequent spermatogonial cell types. Self-renewal of SSCs A continuous supply of differentiating germ cells is essential for spermatogenesis. Atm The protein kinase ataxia telangiectasia-mutated ATM regulates apoptosis and cell cycle checkpoint responses after DNA double-strand breaks DSBs , telomere erosion and oxidative stress Shiloh, Niche for A undiff spermatogonia and blood vessel formation A study from Chiarini-Garcia and colleagues showed A undiff spermatogonia are preferentially localized to the basal area of the tubules adjacent to interstitium and vasculature rather than to regions adjacent to other tubules Chiarini-Garcia et al.
Other factors potentially involved in regulation of SSC self-renewal 3. Gja1 Cx43 Gap junction protein, alpha 1 GJA1 , which is also known as connexin 43 CX43 , is the predominant testicular gap junctional protein located between neighboring Sertoli cells and between Sertoli cells and germ cells Brehm and Steger, Spermatogonial differentiation There are three important regulatory points for spermatogonial differentiation.
Figure 3. Retinoic acid RA RA, a biologically active metabolite of vitamin A retinol , is essential for male fertility Griswold et al. Sohlh1 Spermatogenesis and oogenesis specific basic helix-loop-helix 1 SOHLH1 is a transcription factor preferentially expressed in type A spermatogonia Ballow et al. Sohlh2 Spermatogenesis and oogenesis specific basic helix-loop-helix 1 SOHLH2 is a germ cell specific transcription factor Ballow et al.
Utp14b Jsd In mice that are homozygous for the Jsd mutation, a single wave of spermatogenesis is followed by failure of type A spermatogonia to differentiate, rendering male animals sterile, whereas female animals are apparently normal Boettger-Tong et al. Testosterone Testosterone has no direct impact on germ cell development but indirectly regulates spermatogenesis through Sertoli cells Johnston et al.
Other factors potentially involved in regulation of spermatogonial differentiation 3. Stra8 Stimulated by retinoic acid gene 8 Stra8 was first identified as a gene under RA regulation in several carcinoma cell lines OuladAbdelghani et al. Nanos3 nanos homolog 3 Drosophila Nanos3 encodes for a zinc-finger protein with putative RNA-binding activity. Conclusions Phenotype analyses and mechanistic studies using genetic models have resulted in several major advances in our understanding of spermatogonial self-renewal and differentiation.
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