ATRA and KL promote differentiation toward the meiotic program of male germ cells.

Pellegrini, Manuela; Filipponi, Doria; Gori, Manuele; Barrios, Florencia; Lolicato, Francesca; Grimaldi, Paola; Rossi, Pellegrino; Jannini, Emmanuele A.; Geremia, Raffaele; Dolci, Susanna

doi:10.4161/cc.7.24.7262

Cited by 110 publications

(154 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: 94%

“…2A). In addition, sections of testes from 2-wk-old mice were co-immunostained with antibodies to ZBTB16 and to KIT (Table S1), a marker for differentiated spermatogonia (22). There were little apparent differences in the KIT staining in WT, Het, and cKO mice (Fig.…”

Section: Resultsmentioning

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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Targeting theGdnfGene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Chen

Willis

Eddy

2016

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

154

128

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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: 94%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Targeting theGdnfGene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Chen

Willis

Eddy

2016

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

154

128

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“…Compared with control testes, we found that transcript levels of several important markers of Sertoli cells, such as Sox9, Sox8, Amh, Fgf9 and Dhh, were significantly downregulated in P0 mutant testes, except for Wt1, which was only slightly reduced. We also examined expression levels of genes for Sertoli cell-derived signalling molecules GDNF (glial cell line-derived neurotrophic factor) and FGF2, involved in SSC self-renewal and proliferation (Meng et al 2000;Simon et al 2007), and KL (Kit ligand) and BMP4, involved in SSC differentiation (Pellegrini et al 2003(Pellegrini et al , 2008. Whereas expression levels of Fgf2 were unchanged, Kl and Bmp4 were downregulated by about 40% and Gdnf by about 70%.…”

Section: Altered Gene Expression In Dicer δ δ δ δ δ/δ δ δ δ δ Testes mentioning

confidence: 99%

Dicer is required for Sertoli cell function and survival

Kim¹,

Georg²,

Scherthan³

et al. 2010

Int. J. Dev. Biol.

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Dicer is a key enzyme that processes microRNA precursors into their mature form, enabling them to regulate gene expression. Dicer null mutants die before gastrulation. To study Dicer function in testis development, we crossed mice carrying a conditional Dicer allele with an AMH-Cre transgenic line, thereby inactivating Dicer in Sertoli cells around embryonic day 14.0 (E14.0). Dicer null Sertoli cells show normal embryonic development, and at postnatal day 0 (P0), testis tubules are normal in number and histologically undistinguishable from controls. Subsequently, Dicer-mutant testes show a progressively aberrant development, so that at P6, they contain a reduced number of disorganized testis tubules leading to primary sterility. Apoptosis and prophase I assays reveal a massive wave of apoptosis starting at P3, causing progressive loss of Sertoli cells, but also of germ cells, resulting in drastically reduced testis size. Expression of genes that play crucial roles in testis development, structural integrity and spermatogenesis is downregulated at P0, before morphological changes become apparent, indicating that Dicer-mutant testes are already transcriptionally compromised at this stage. Taken together, the results of this study show that Dicer is required for Sertoli cell function and survival and for spermatogenesis in mice.

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“…as Bone Morphogenetic Protein 4, stimulate Kit expression in undifferentiated spermatogonia (Pellegrini et al, 2003;Pellegrini et al, 2008;Zhou et al, 2008). The full-length KIT protein is also expressed in post-natal oocytes, and several reports indicate that it is important for their growth and maturation (Packer et al, 1994;Kissel et al, 2000;Klinger and De Felici, 2002;Hutt et al, 2006).…”

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confidence: 99%

Transcriptional control of KIT gene expression during germ cell development

Rossi¹

2013

Int. J. Dev. Biol.

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The characterization of the mechanisms that regulate KIT expression in germ cells at different times of their development is important not only in the field of reproduction, but also for a better understanding of the biology of testicular germ cell tumors (TGCTs). Indeed this tyrosine kinase receptor, besides being essential for the survival and proliferation of primordial germ cells (PGCs) and for postnatal spermatogenesis and oogenesis, is also frequently overexpressed or constitutively active due to activating mutations in carcinoma in situ of the testis and in seminomas. In this review, I will summarize available data about the transcriptional mechanisms involved in the control of Kit expression in the germline. Variable mechanisms, involving different germ cell-specific transcription factors, are operating in the various developmental stages: SOX2 and SOHLH1/2 act as direct positive regulators in PGCs and in postnatal spermatogonia, respectively, whereas PLZF suppresses KIT expression in spermatogonial stem cells. DMRT1, acting through indirect mechanisms, suppresses KIT transcription in fetal gonocytes, while activating it in differentiating spermatogonia.

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ATRA and KL promote differentiation toward the meiotic program of male germ cells.

Cited by 110 publications

References 43 publications

Targeting theGdnfGene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Targeting theGdnfGene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Dicer is required for Sertoli cell function and survival

Transcriptional control of KIT gene expression during germ cell development

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