FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of<i>Etv5</i>and<i>Bcl6b</i>through MAP2K1 activation

Ishii, Kei; Kanatsu-Shinohara, Mito; Toyokuni, Shinya; Shinohara, Takashi

doi:10.1242/dev.076539

Cited by 187 publications

(187 citation statements)

References 30 publications

Supporting

Mentioning

182

Contrasting

Order By: Relevance

“…Colony stimulating factor 1 (CSF1) is produced by Leydig and PM cells and enhanced the self-renewal of SSCs in vitro in the presence of GDNF (40), as did fibroblast growth factor 2 (FGF2) (26,37,55), whose transcripts were identified in Sertoli cells (56,57). Sertoli cells are recognized to have a key role in forming the niche and in determining the number of niches and SSCs in the testis (58).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting theGdnfGene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Chen

Willis

Eddy

2016

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

157

128

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

“…FGF2 is expressed by Sertoli cells and was reported to enhance the ability of GDNF to maintain SSC proliferation in vitro (26,32,36,37). However, no significant differences were detected by ELISA in FGF2 protein levels in testes of 8-wk-old WT, Het, and cKO mice (Fig.…”

Section: Effects Of Cko On Genes Involved In Spermatogonial Developmentmentioning

confidence: 91%

Targeting theGdnfGene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Chen

Willis

Eddy

2016

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

157

128

View full text Add to dashboard Cite

show abstract

“…The development of mouse GSC cultures was a huge advance for GSC research, since they allowed studying the direct effect of cytokines (Kanatsu-Shinohara et al, 2005) and chemokines (Dovere et al, 2013) on GSCs in vitro, which correspond to the SSC population in situ. Consequently, downstream signaling pathways of cytokines and chemokines and the transcriptional regulation of SSCs could be analyzed for the first time using these in vitro systems (Braydich-Stolle et al, 2007;Lee et al, 2007;Oatley et al, 2007;Ishii et al, 2012). Apart from that, the in vitro reconstruction of SSC niches allowed investigating the effect of specific niche factors .…”

Section: Introductionmentioning

confidence: 99%

Male germline stem cells in non-human primates

Sharma¹,

Portela

Langenstroth-Röwer³

et al. 2017

Primate Biol.

View full text Add to dashboard Cite

Abstract.Over the past few decades, several studies have attempted to decipher the biology of mammalian germline stem cells (GSCs). These studies provide evidence that regulatory mechanisms for germ cell specification and migration are evolutionarily conserved across species. The characteristics and functions of primate GSCs are highly distinct from rodent species; therefore the findings from rodent models cannot be extrapolated to primates. Due to limited availability of human embryonic and testicular samples for research purposes, two non-human primate models (marmoset and macaque monkeys) are extensively employed to understand human germline development and differentiation. This review provides a broader introduction to the in vivo and in vitro germline stem cell terminology from primordial to differentiating germ cells. Primordial germ cells (PGCs) are the most immature germ cells colonizing the gonad prior to sex differentiation into testes or ovaries. PGC specification and migratory patterns among different primate species are compared in the review. It also reports the distinctions and similarities in expression patterns of pluripotency markers (OCT4A, NANOG, SALL4 and LIN28) during embryonic developmental stages, among marmosets, macaques and humans. This review presents a comparative summary with immunohistochemical and molecular evidence of germ cell marker expression patterns during postnatal developmental stages, among humans and non-human primates. Furthermore, it reports findings from the recent literature investigating the plasticity behavior of germ cells and stem cells in other organs of humans and monkeys. The use of non-human primate models would enable bridging the knowledge gap in primate GSC research and understanding the mechanisms involved in germline development. Reported similarities in regulatory mechanisms and germ cell expression profile in primates demonstrate the preclinical significance of monkey models for development of human fertility preservation strategies.

show abstract

“…It is now considered that GDNF activates Harvey rat sarcoma virus oncogene (HRAS) via Src family kinase molecules, and cells transfected with activated HRAS underwent self-renewal division without exogenous cytokines (7). Chemical inhibition of thymoma viral proto-oncogene (AKT) or mitogen-activated protein kinase kinase 1 (MAP2K1), both of which are downstream molecules of HRAS, abrogated GS cell proliferation (8)(9)(10), suggesting that they are necessary for selfrenewal division. When active Akt or Map2k1 was overexpressed in GS cells, Akt-or Map2k1-transfected cells could proliferate with only fibroblast growth factor 2 (FGF2) or GDNF, respectively (8,9).…”

mentioning

confidence: 99%

“…Chemical inhibition of thymoma viral proto-oncogene (AKT) or mitogen-activated protein kinase kinase 1 (MAP2K1), both of which are downstream molecules of HRAS, abrogated GS cell proliferation (8)(9)(10), suggesting that they are necessary for selfrenewal division. When active Akt or Map2k1 was overexpressed in GS cells, Akt-or Map2k1-transfected cells could proliferate with only fibroblast growth factor 2 (FGF2) or GDNF, respectively (8,9). These signals up-regulate Etv5 and Bcl6b (8,11), which work in combination with other constitutively expressed transcription factors, such as zinc finger and BTB domain containing 16 (Zbtb16) or Taf4b, to drive SSC self-renewal.…”

mentioning

confidence: 99%

Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal

Kanatsu-Shinohara

Onoyama

Nakayama

et al. 2014

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

Self Cite

View full text Add to dashboard Cite

Spermatogonial stem cells (SSCs) undergo self-renewal divisions to support spermatogenesis throughout life. Although several positive regulators of SSC self-renewal have been discovered, little is known about the negative regulators. Here, we report that F-box and WD-40 domain protein 7 (FBXW7), a component of the Skp1-Cullin-F-box-type ubiquitin ligase, is a negative regulator of SSC self-renewal. FBXW7 is expressed in undifferentiated spermatogonia in a cell cycle-dependent manner. Although peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1), essential for spermatogenesis, is thought to destroy FBXW7, Pin1 depletion decreased FBXW7 expression. Spermatogonial transplantation showed that Fbxw7 overexpression compromised SSC activity whereas Fbxw7 deficiency enhanced SSC colonization and caused accumulation of undifferentiated spermatogonia, suggesting that the level of FBXW7 is critical for self-renewal and differentiation. Screening of putative FBXW7 targets revealed that Fbxw7 deficiency up-regulated myelocytomatosis oncogene (MYC) and cyclin E1 (CCNE1). Although depletion of Myc/Mycn or Ccne1/Ccne2 compromised SSC activity, overexpression of Myc, but not Ccne1, increased colonization of SSCs. These results suggest that FBXW7 regulates SSC self-renewal in a negative manner by degradation of MYC.

show abstract

FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation ofEtv5andBcl6bthrough MAP2K1 activation

Cited by 187 publications

References 30 publications

Targeting theGdnfGene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Targeting theGdnfGene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Male germline stem cells in non-human primates

Skp1-Cullin-F-box (SCF)-type ubiquitin ligase FBXW7 negatively regulates spermatogonial stem cell self-renewal

Contact Info

Product

Resources

About