The Transition from Stem Cell to Progenitor Spermatogonia and Male Fertility Requires the SHP2 Protein Tyrosine Phosphatase

Puri, Pawan; Phillips, Bart; Suzuki, Hitomi; Orwig, Kyle E.; Rajkovic, Aleksandar; Lapinski, Philip E.; King, Philip D.; Feng, Gen Sheng; Walker, William H.

doi:10.1002/stem.1572

Cited by 42 publications

(37 citation statements)

References 48 publications

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“…Specifically: (a) both YAP1 and CD133, NANOG and OCT-3/4 stem cell markers are overexpressed in HCC, and their expression is higher in more aggressive tumors exhibiting higher growth rate and lower apoptosis; (b) NANOG and OCT-3/4 protein levels are statistically correlated with YAP1 and YAP1-TEAD levels in HCC; (c) forced YAP1 overexpression in liver tumor cell lines induces consistent increase of CD133, NANOG and OCT-3/4 expression, cell viability, migration and invasivity, whereas YAP1 inhibition by specific siRNA leads to opposite changes; (d) stem cell markers overexpression does not occur in cancer cell lines transfected with mutant YAP1 that does not form complexes with TEAD [23]. Remarkably, microarray analysis showed that forced YAP1 overexpression in Huh7 cells resulted in increased expression of genes that mediate the acquisition of a stem cells phenotype in cancer of liver and/or other tissues, including MAP2K5 [32, 33] , PPM1A [34], PTPN11 [35], PTPRM [36], PDE2A [37] IRF2 [38], LDHA [39] SH3KBP1 [40] and SPSB1 [41]. Interestingly, the expression of MAP2K5, PPM1A, PTPN11, and SPSB1 revealed a sharp increase especially in more aggressive HCCP exhibiting highest expression of stem cell markers, as well as in HepG2 cells transfected with YAP1.…”

Section: Discussionmentioning

confidence: 99%

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

et al. 2016

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Previous studies showed that YAP1 is over-expressed in hepatocellular carcinoma (HCC). Here we observed higher expression of Yap1/Ctgf axis in dysplastic nodules and HCC chemically-induced in F344 rats, genetically susceptible to hepatocarcinogenesis, than in lesions induced in resistant BN rats. In BN rats, highest increase in Yap1-tyr357, p73 phosphorylation and Caspase 3 cleavage occurred. In human HCCs with poorer prognosis (< 3 years survival after partial liver resection, HCCP), levels of YAP1, CTGF, 14–3–3, and TEAD proteins, and YAP1-14-3-3 and YAP1-TEAD complexes were higher than in HCCs with better outcome (> 3 years survival; HCCB). In the latter, higher levels of phosphorylated YAP1-ser127, YAP1-tyr357 and p73, YAP1 ubiquitination, and Caspase 3 cleavage occurred. Expression of stemness markers NANOG, OCT-3/4, and CD133 were highest in HCCP and correlated with YAP1 and YAP1-TEAD levels. In HepG2, Huh7, and Hep3B cells, forced YAP1 over-expression led to stem cell markers expression and increased cell viability, whereas inhibition of YAP1 expression by specific siRNA, or transfection of mutant YAP1 which does not bind to TEAD, induced opposite alterations. These changes were associated, in Huh7 cells transfected with YAP1 or YAP1 siRNA, with stimulation or inhibition of cell migration and invasivity, respectively. Furthermore, transcriptome analysis showed that YAP1 transfection in Huh7 cells induces over-expression of genes involved in tumor stemness. In conclusion, Yap1 post-translational modifications favoring its ubiquitination and apoptosis characterize HCC with better prognosis, whereas conditions favoring the formation of YAP1-TEAD complexes are associated with aggressiveness and acquisition of stemness features by HCC cells.

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Section: Discussionmentioning

confidence: 99%

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

et al. 2016

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“…and SRC family kinase pathways (Airaksinen & Saarma 2002, Oatley et al 2007, Lee et al 2007, He et al 2008. SHP2 protein tyrosine phosphatase encoded by the Ptpn11 (protein tyrosine phosphatase, non-receptor type 11) gene is a key regulator of GDNF signaling within SSCs (Puri et al 2014). Deletion of GDNF receptor components triggers rapid SSC depletion resulting in a Sertoli-cell-only phenotype (Meng et al 2000, Naughton et al 2006.…”

Section: Gdnfmentioning

confidence: 99%

Molecular regulation of spermatogonial stem cell renewal and differentiation

Mäkelä

Hobbs

2019

Reproduction

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The intricate molecular and cellular interactions between spermatogonial stem cells (SSCs) and their cognate niche form the basis for life-long sperm production. To maintain long-term fertility and sustain sufficiently high levels of spermatogenesis, a delicate balance needs to prevail between the different niche factors that control cell fate decisions of SSCs by promoting self-renewal, differentiation priming or spermatogenic commitment of undifferentiated spermatogonia (A undiff ). Previously the SSC niche was thought to be formed primarily by Sertoli cells. However, recent research has indicated that many distinct cell types within the testis contribute to the SSC niche including most somatic cell populations and differentiating germ cells. Moreover, postnatal testis development involves maturation of somatic supporting cell populations and onset of cyclic function of the seminiferous epithelium. The stochastic and flexible behavior of A undiff further complicates the definition of the SSC niche. Unlike in invertebrate species, providing a simple anatomical description of the SSC niche in the mouse is therefore challenging. Rather, the niche needs to be understood as a dynamic system that is able to serve the long-term reproductive function and maintenance of fertility both under steady-state and during development plus regeneration. Recent data from us and others have also shown that A undiff reversibly transition between differentiation-primed and self-renewing states based on availability of niche-derived cues. This review focuses on defining the current understanding of the SSC niche and the elements involved in its regulation.Reproduction (2019) 158 R169-R187 J-A Mäkelä and R M Hobbs R170 Reproduction (2019) 158 R169-R187 https://rep.bioscientifica.com SSC niche in mice R171 https://rep.bioscientifica.com Reproduction (2019) 158 R169-R187 J-A Mäkelä and R M Hobbs R172 Reproduction (2019) 158 R169-R187 https://rep.bioscientifica.com SSC niche in mice R173 https://rep.bioscientifica.com Reproduction (2019) 158 R169-R187 J-A Mäkelä and R M Hobbs R174 Reproduction (2019) 158 R169-R187 https://rep.bioscientifica.com J-A Mäkelä and R M Hobbs R176 Reproduction (2019) 158 R169-R187

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“…Moreover, the absence of a new wave of spermatogenesis showed that self-renewal of SSCs is impaired in the absence of PELO. The dramatic disruption of spermatogenesis in Pelo-deficient mice is similar to that observed in mice lacking the Plzf, Etv5, Foxo1, or Shp2 genes, which regulate the self-renewal of SSCs (Costoya et al 2004, Simon et al 2007, Goertz et al 2011, Puri et al 2014.…”

Section: Discussionmentioning

confidence: 52%

Pelota mediates gonocyte maturation and maintenance of spermatogonial stem cells in mouse testes

Raju¹,

Nyamsuren²,

Elkenani³

et al. 2015

Reproduction

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Pelota (Pelo) is an evolutionarily conserved gene, and its deficiency in Drosophila affects both male and female fertility. In mice, genetic ablation of Pelo leads to embryonic lethality at the early implantation stage as a result of the impaired development of extra-embryonic endoderm (ExEn). To define the consequences of Pelo deletion on male germ cells, we temporally induced deletion of the gene at both embryonic and postnatal stages. Deletion of Pelo in adult mice resulted in a complete loss of whole-germ cell lineages after 45 days of deletion. The absence of newly emerging spermatogenic cycles in mutants confirmed that spermatogonial stem cells (SSCs) were unable to maintain spermatogenesis in the absence of PELO protein. However, germ cells beyond the undifferentiated SSC stage were capable of completing spermatogenesis and producing spermatozoa, even in the absence of PELO. Following the deletion of Pelo during embryonic development, we found that although PELO is dispensable for maintaining gonocytes, it is necessary for the transition of gonocytes to SSCs. Immunohistological and protein analyses revealed the attenuation of FOXO1 transcriptional activity, which induces the expression of many SSC self-renewal genes. The decreased transcriptional activity of FOXO1 in mutant testes was due to enhanced activity of the PI3K/AKT signaling pathway, which led to phosphorylation and cytoplasmic sequestration of FOXO1. These results suggest that PELO negatively regulates the PI3K/AKT pathway and that the enhanced activity of PI3K/AKT and subsequent FOXO1 inhibition are responsible for the impaired development of SSCs in mutant testes.

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The Transition from Stem Cell to Progenitor Spermatogonia and Male Fertility Requires the SHP2 Protein Tyrosine Phosphatase

Cited by 42 publications

References 48 publications

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

Post-translational deregulation of YAP1 is genetically controlled in rat liver cancer and determines the fate and stem-like behavior of the human disease

Molecular regulation of spermatogonial stem cell renewal and differentiation

Pelota mediates gonocyte maturation and maintenance of spermatogonial stem cells in mouse testes

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