The heterogeneity of spermatogonia is revealed by their topology and expression of marker proteins including the germ cell-specific proteins Nanos2 and Nanos3

Suzuki, Hitomi; Sada, Aiko; Yoshida, Shosei; Saga, Yumiko

doi:10.1016/j.ydbio.2009.10.002

Cited by 179 publications

(190 citation statements)

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“…SSCs share molecular markers with undifferentiated spermatogonia (13)(14)(15)(16)(17), and these markers were expressed at significantly higher levels at 1 wk after birth in the testes of WT mice than in cKO mice. However, molecular markers for differentiated spermatogonia (18)(19)(20)(21)(22) were present at significantly higher levels at 1 wk after birth in cKO mice than in WT mice. In addition, germ cells containing the ZBTB16 marker for SSCs and undifferentiated spermatogonia (15) were detected by immunohistochemistry in 2-wk-old WT mice, but rarely in cKO males, and some of their tubules lack proliferating germ cells.…”

Section: Discussionmentioning

confidence: 99%

“…SSCs also share molecular markers with undifferentiated spermatogonia, including Nanos2, Gfra1, Zbtb16, Bcl6b, and THY1 (13)(14)(15)(16)(17). In addition, differentiating spermatogonia have characteristic molecular markers, including Ngn3, Nanos3, Spo11, and KIT (18)(19)(20)(21)(22). These molecular markers have been proven to be valuable tools for monitoring the presence or absence of different populations of spermatogonia.…”

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confidence: 99%

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Targeting the Gdnf Gene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Chen

Willis

Eddy

2016

Proc. Natl. Acad. Sci. U.S.A.

151

123

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Spermatogonial stem cells (SSCs) are a subpopulation of undifferentiated spermatogonia located in a niche at the base of the seminiferous epithelium delimited by Sertoli cells and peritubular myoid (PM) cells. SSCs self-renew or differentiate into spermatogonia that proliferate to give rise to spermatocytes and maintain spermatogenesis. Glial cell line-derived neurotrophic factor (GDNF) is essential for this process. Sertoli cells produce GDNF and other growth factors and are commonly thought to be responsible for regulating SSC development, but limited attention has been paid to the role of PM cells in this process. A conditional knockout (cKO) of the androgen receptor gene in PM cells resulted in male infertility. We found that testosterone (T) induces GDNF expression in mouse PM cells in vitro and neonatal spermatogonia (including SSCs) co-cultured with T-treated PM cells were able to colonize testes of germ cell-depleted mice after transplantation. This strongly suggested that T-regulated production of GDNF by PM cells is required for spermatogonial development, but PM cells might produce other factors in vitro that are responsible. In this study, we tested the hypothesis that production of GDNF by PM cells is essential for spermatogonial development by generating mice with a cKO of the Gdnf gene in PM cells. The cKO males sired up to two litters but became infertile due to collapse of spermatogenesis and loss of undifferentiated spermatogonia. These studies show for the first time, to our knowledge, that the production of GDNF by PM cells is essential for undifferentiated spermatogonial cell development in vivo.spermatogonial stem cell | stem cell niche | male fertility | spermatogenesis | conditional gene targeting T he seminiferous epithelium is separated by tight junctions between Sertoli cells into a luminal compartment containing spermatocytes and spermatids and a basal compartment containing spermatogonial stem cells (SSCs) and spermatogonia. The basal compartment is bounded above and on the sides by Sertoli cells and below by the basement membrane of the seminiferous tubule and a layer of peritubular myoid (PM) cells. SSCs are thought to reside in a microenvironmental niche in the basal compartment, where extrinsic cues influence their decision to either self-renew or enter the pathway of spermatogonial development (1, 2). They are a minor fraction of the undifferentiated spermatogonia in the basal compartment. The other undifferentiated spermatogonia (progenitors) give rise to differentiating spermatogonia that proliferate mitotically to progress on a developmental pathway toward becoming spermatocytes (3, 4). Our current understanding of the progression of SSCs to differentiating spermatogonia comes mainly from cell kinetic studies, germ cell transplantation assays, and the use of molecular markers that identify different populations of spermatogonia.The leading model for spermatogonial development specifies that when SSCs divide, they either self-renew by becoming two type A-single (A s ) spermato...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Targeting the Gdnf Gene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Chen

Willis

Eddy

2016

Proc. Natl. Acad. Sci. U.S.A.

151

123

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“…C , KIT -mouse germ cells express high levels of NANOS2, a RNA-binding protein involved in SSC self-renewal and in the suppression of spermatogonial differentiation (Suzuki & Saga 2008, Suzuki et al 2009, Sada et al 2012, in response to FGF9, a growth factor produced by Sertoli cells (Barrios et al 2010). By contrast, the addition of RA reduced NANOS2 expression and concomitantly induced KIT and STRA8 expression in these cells (Barrios et al 2010).…”

Section: Spermatogonia and Ssc Differentiationmentioning

confidence: 99%

“…These studies unveiled the co-existence of two distinct populations within the Ngn3 C undifferentiated (A single , A pair , and A aligned ) spermatogonia, one constituting true SSCs and the other corresponding to a transit amplifying population of cells ('potential stem cells') that retained the ability to self-renew in specific conditions, where the replenishment of the SSC pool was required. However, a later study using additional markers proposed that true SSCs are included among a group of Ngn3 K undifferentiated spermatogonia, and that NGN3 C spermatogonia represent transit amplifying progenitor spermatogonia issued from the SSCs (Suzuki et al 2009). This difference illustrates a recurring problem linked to the difficulty of establishing definitive SSC identity (Hermann et al 2011).…”

Section: Spermatogonia and Ssc Differentiationmentioning

confidence: 99%

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

Manku¹,

Culty²

2015

Reproduction

123

105

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The production of spermatozoa relies on a pool of spermatogonial stem cells (SSCs), formed in infancy from the differentiation of their precursor cells, the gonocytes. Throughout adult life, SSCs will either self-renew or differentiate, in order to maintain a stem cell reserve while providing cells to the spermatogenic cycle. By contrast, gonocytes represent a transient and finite phase of development leading to the formation of SSCs or spermatogonia of the first spermatogenic wave. Gonocyte development involves phases of quiescence, cell proliferation, migration, and differentiation. Spermatogonia, on the other hand, remain located at the basement membrane of the seminiferous tubules throughout their successive phases of proliferation and differentiation. Apoptosis is an integral part of both developmental phases, allowing for the removal of defective cells and the maintenance of proper germ-Sertoli cell ratios. While gonocytes and spermatogonia mitosis are regulated by distinct factors, they both undergo differentiation in response to retinoic acid. In contrast to postpubertal spermatogenesis, the early steps of germ cell development have only recently attracted attention, unveiling genes and pathways regulating SSC self-renewal and proliferation. Yet, less is known on the mechanisms regulating differentiation. The processes leading from gonocytes to spermatogonia have been seldom investigated. While the formation of abnormal gonocytes or SSCs could lead to infertility, defective gonocyte differentiation might be at the origin of testicular germ cell tumors. Thus, it is important to better understand the molecular mechanisms regulating these processes. This review summarizes and compares the present knowledge on the mechanisms regulating mammalian gonocyte and spermatogonial differentiation.

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“…The expression profile of CDH1, LIN28, GFRA1, NANOS2, NANOS3 and NEUROG3 (NGN3) is heterogeneous among As, Apr and Aal spermatogonia (Grisanti et al 2009, Suzuki et al 2009, Zheng et al 2009, Nakagawa et al 2010; moreover, different subsets of As cells may be generated through an asymmetric division (Grisanti et al 2009, Suzuki et al 2009). Data from transgenic animal models were interpreted to mean that two functionally distinct stem cell compartments exist: the actual and the potential stem cell compartments, which may play different roles in different conditions.…”

Section: Introductionmentioning

confidence: 99%

Distribution of GFRA1-expressing spermatogonia in adult mouse testis

Grasso¹,

Fuso²,

Dovere³

et al. 2012

Reproduction

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In mice and other mammals, spermatogenesis is maintained by spermatogonial stem cells (SSCs), a cell population belonging to undifferentiated type A spermatogonia. In the accepted model of SSC self-renewal, Asingle (As) spermatogonia are the stem cells, whereas paired (Apaired (Apr)) and chained (Aaligned (Aal)) undifferentiated spermatogonia are committed to differentiation. This model has been recently challenged by evidence that As and chained (Apr and Aal), undifferentiated spermatogonia are heterogeneous in terms of gene expression and function. The expression profile of several markers, such as GFRA1 (the GDNF co-receptor), is heterogeneous among As, Apr and Aal spermatogonia. In this study, we have analysed and quantified the distribution of GFRA1-expressing cells within the different stages of the seminiferous epithelial cycle. We show that in all stages, GFRA1C chained spermatogonia (Apr to Aal) are more numerous than GFRA1C As spermatogonia. Numbers of chained GFRA1C spermatogonia are sharply reduced in stages VII-VIII when Aal differentiate into A1 spermatogonia. GFRA1 expression is regulated by GDNF and in cultures of isolated seminiferous tubules, we found that GDNF expression and secretion by Sertoli cells is stage-dependent, being maximal in stages II-VI and decreasing thereafter. Using qRT-PCR analysis, we found that GDNF regulates the expression of genes such as Tex14, Sohlh1 and Kit (c-Kit) known to be involved in spermatogonial differentiation. Expression of Kit was upregulated by GDNF in a stage-specific manner. Our data indicate that GDNF, besides its crucial role in the self-renewal of stem cells also functions in the differentiation of chained undifferentiated spermatogonia.

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The heterogeneity of spermatogonia is revealed by their topology and expression of marker proteins including the germ cell-specific proteins Nanos2 and Nanos3

Cited by 179 publications

References 31 publications

Targeting the Gdnf Gene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Targeting the Gdnf Gene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

Distribution of GFRA1-expressing spermatogonia in adult mouse testis

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