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Query: EC:2.7.10.1 (ERK)
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Human testicular germ cell tumours of adolescents and adults (TGCTs), including their precursor lesion carcinoma in situ (CIS), show expression of a 1.5 kb alternative transcript of the platelet-derived growth factor (PDGF) alpha-receptor gene. The so-called P2 promoter involved is located in intron 12 and its activity was found to be mutually exclusive with activity of the classical promoter (P1), which encodes the full-length receptor. The presence of the 1.5 kb transcript could be a putative marker for the early molecular diagnosis of TGCTs. In order to validate the RT-PCR approach, this study shows that not more than 100 transcripts are necessary to obtain positivity in the test used; moreover, samples from TGCTs or CIS-containing tissues can be diluted many-fold before resulting in false-negative findings. This study also shows that within TGCTs, as in TGCT-derived cell lines, expression of the 1.5 kb transcript is differentiation-dependent and positively correlated with expression of the embryonic transcription factor OCT-4/POU5F1. Furthermore, the results indicate that in some non-TGCT cancers and cell lines the 1.5 kb transcript is also expressed, but without concomitant OCT-4/POU5F1 expression. The 1.5 kb transcript is also present in early B cells and derived leukaemias (B-ALL). In spite of similarities in chromosomal location, down-regulation upon differentiation of TGCTs, and PDGF alpha-receptor and c-KIT (the stem cell factor receptor) both being a tyrosine kinase receptor, no correlation was found between activity of the P2 promoter of the PDGF alpha-receptor gene and expression of c-KIT. In conclusion, the 1.5 kb transcript of the PDGF alpha-receptor is expressed in various cells and tissues, including particular blood cells. Although this may hamper the use of this transcript as a marker for malignancies in general, it does not appear to interfere with assays for the early detection of TGCTs.
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PMID:Expression of the PDGF alpha-receptor 1.5 kb transcript, OCT-4, and c-KIT in human normal and malignant tissues. Implications for the early diagnosis of testicular germ cell tumours and for our understanding of regulatory mechanisms. 1192 Jul 44

Spermatogonial stem cells (SSCs) are essential for spermatogenesis, and these adult tissue stem cells balance self-renewal and differentiation to meet the biological demand of the testis. The developmental dynamics of SSCs are controlled, in part, by factors in the stem cell niche, which is located on the basement membrane of seminiferous tubules situated among Sertoli cells. Sertoli cells produce glial cell line-derived neurotrophic factor (GDNF), and disruption of GDNF expression results in spermatogenic defects and infertility. The GDNF signals through a receptor complex that includes GDNF family receptor alpha1 (GFRA1), which is thought to be expressed by SSCs. However, expression of GFRA1 on SSCs has not been confirmed by in vivo functional assay, which is the only method that allows definitive identification of SSCs. Therefore, we fractionated mouse pup testis cells based on GFRA1 expression using magnetic activated cell sorting. The sorted and depleted fractions of GFRA1 were characterized for germ cell markers by immunocytochemistry and for stem cell activity by germ cell transplantation. The GFRA1-positive cell fraction coeluted with other markers of SSCs, including ITGA6 and CD9, and was significantly depleted of KIT-positive cells. The transplantation results confirmed that a subpopulation of SSCs expresses GFRA1, but also that the stem cell pool is heterogeneous with respect to the level of GFRA1 expression. Interestingly, POU5F1-positive cells were enriched nearly 15-fold in the GFRA1-selected fraction, possibly suggesting heterogeneity of developmental potential within the stem cell pool.
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PMID:GDNF family receptor alpha1 phenotype of spermatogonial stem cells in immature mouse testes. 1601 11

Germ cell tumors (GCTs) of the testis are the predominant cancer among young men. We analyzed gene expression profiles of 50 GCTs of various subtypes, and we compared them with 443 other common malignant tumors of epithelial, mesenchymal, and lymphoid origins. Significant differences in gene expression were found among major histological subtypes of GCTs, and between them and other malignancies. We identified 511 genes, belonging to several critical functional groups such as cell cycle progression, cell proliferation, and apoptosis, to be significantly differentially expressed in GCTs compared with other tumor types. Sixty-five genes were sufficient for the construction of a GCT class predictor of high predictive accuracy (100% training set, 96% test set), which might be useful in the diagnosis of tumors of unknown primary origin. Previously described diagnostic and prognostic markers were found to be expressed by the appropriate GCT subtype (AFP, POU5F1, POV1, CCND2, and KIT). Several additional differentially expressed genes were identified in teratomas (EGR1 and MMP7), yolk sac tumors (PTPN13 and FN1), and seminomas (NR6A1, DPPA4, and IRX1). Dynamic computation of interaction networks and mapping to existing pathways knowledge databases revealed a potential role of EGR1 in p21-induced cell cycle arrest and intrinsic chemotherapy resistance of mature teratomas.
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PMID:Gene expression profiling differentiates germ cell tumors from other cancers and defines subtype-specific signatures. 1630 58

Canonical WNT signals are transduced through Frizzled (FZD) family receptor and LRP5/LRP6 co-receptor to upregulate FGF20, JAG1, DKK1, WISP1, CCND1 and MYC genes for cell-fate determination, while non-canonical WNT signals are transduced through FZD family receptor and ROR2/PTK7/RYK co-receptor to activate RHOA/RHOU/RAC/CDC42, JNK, PKC, NLK and NFAT signaling cascades for the regulation of tissue polarity, cell movement, and adhesion. We previously reported molecular cloning and characterization of human FZD5, which showed six amino-acid substitutions with human Hfz5. FZD5, functioning as WNT5A receptor, is the key molecule in the fields of oncology, regenerative medicine, cardiology, rheumatology, diabetology, and gastroenterology. Here, comparative integromics analyses on FZD5 orthologs were performed by using bioinformatics (Techint) and human intelligence (Humint). Chimpanzee FZD5 and cow Fzd5 genes were identified within NW_104292.1 and AC166656.2 genome sequences, respectively. FZD5 orthologs were seven-transmembrane proteins with extracellular Frizzled domain, leucine zipper motif around the 5th transmembrane domain, and cytoplasmic DVL- and PDZ-binding motifs. Ser523 and Ser529 around the DVL-binding motif of FZD5 orthologs were putative aPKC phosphorylation sites. POU5F1 (OCT4)-binding site linked to SP1-binding site within the 5'-promoter region of human FZD5 gene was evolutionarily conserved among mammalian FZD5 orthologs. POU5F1 was more related to POU2F and POU3F subfamily members. POU5F1 was preferentially expressed in undifferentiated human embryonic stem (ES) cells, pancreatic islet, and diffuse-type gastric cancer. POU2F1 (OCT1) was expressed in ES cells, fetal liver/spleen, adult colon, POU2F2 in ES cells, fetal liver/spleen, and POU2F3 in diffuse-type gastric cancer. Multiple SP1/KLF family members, other than KLF2 or KLF4, were expressed in undifferentiated human ES cells. Together, these facts indicate that POU5F1 and POU2F subfamily members play a pivotal role for the FZD5 expression in undifferentiated human ES cells, fetal liver/spleen, adult colon, pancreatic islet, and diffuse-type gastric cancer.
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PMID:Conserved POU-binding site linked to SP1-binding site within FZD5 promoter: Transcriptional mechanisms of FZD5 in undifferentiated human ES cells, fetal liver/spleen, adult colon, pancreatic islet, and diffuse-type gastric cancer. 1727 78

Spermatogenesis is the process by which spermatogonial stem cells divide and differentiate into sperm. The role of growth factor receptors in regulating self-renewal and differentiation of spermatogonial stem cells remains largely unclear. This study was designed to examine Gfra1 receptor expression in immature and adult mouse testes and determine the effects of Gfra1 knockdown on the proliferation and differentiation of type A spermatogonia. We demonstrated that GFRA1 was expressed in a subpopulation of spermatogonia in immature and adult mice. Neither Gfra1 mRNA nor GFRA1 protein was detected in pachytene spermatocytes and round spermatids. GFRA1 and POU5F1 (also known as OCT4), a marker for spermatogonial stem cells, were co-expressed in a subpopulation of type A spermatogonia from 6-day-old mice. In addition, the spermatogonia expressing GFRA1 exhibited a potential for proliferation and the ability to form colonies in culture, which is a characteristic of stem cells. RNA interference assays showed that Gfra1 small interfering RNAs (siRNAs) knocked down the expression of Gfra1 mRNA and GFRA1 protein in type A spermatogonia. Notably, the reduction of Gfra1 expression by Gfra1 siRNAs induced a phenotypic differentiation, as evidenced by the elevated expression of KIT, as well as the decreased expression of POU5F1 and proliferating cell nuclear antigen (PCNA). Furthermore, Gfra1 silencing resulted in a decrease in RET phosphorylation. Taken together, these data indicate that Gfra1 is expressed dominantly in mouse spermatogonial stem cells and that Gfra1 knockdown leads to their differentiation via the inactivation of RET tyrosine kinase, suggesting an essential role for Gfra1 in spermatogonial stem cell regulation.
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PMID:Gfra1 silencing in mouse spermatogonial stem cells results in their differentiation via the inactivation of RET tyrosine kinase. 1762 9

Non-canonical WNT and planar cell polarity (PCP) are overlapping but distinct signaling pathways, which control convergent extension, neural tube closure, orientation of cilia and sensory hair cells, axon guidance, and cell motility. Non-canonical WNT signals, regulated by the interaction of WNT, WNT antagonist, Frizzled and ROR2, are transduced to JNK, ROCK, PKC, MAP3K7, and NFAT signaling cascades. PCP signals, regulated by the interaction of VANGL-PRICKLE complex, CELSR and Frizzled-DVL complex, are transduced to JNK, ROCK, and other uncharacterized signaling cascades. PTK7 signaling, regulated by SEMA6 and Plexin-A family members, affects PCP pathway through VANGL. Here, integrative genomic analyses on WNT5A, WNT5B, WNT11, FZD3, FZD6, ROR1, ROR2, RYK, CELSR1, CELSR2, CELSR3, VANGL1, VANGL2, PRICKLE1, PRICKLE2, PTK7, SEMA6A, SEMA6B, SEMA6C and SEMA6D were carried out. PTK7 and SEMA6A were expressed in undifferentiated embryonic stem (ES) cells, SEMA6A in endodermal progenitors, CELSR1, VANGL1 and PTK7 in gastrointestinal tumors. CELSR2, PRICKLE2 and SEMA6C were expressed in fetal brain, CELSR2, PRICKLE1 and SEMA6A in adult brain, WNT5A and CELSR3 in adult brain tumors. These facts indicate class switches of non-canonical WNT or PCP signaling molecules during embryogenesis and carcinogenesis. TCF/LEF-, SP1-, and 5 bHLH-binding sites within human PTK7 promoter were conserved in chimpanzee, rhesus monkey, mouse, and rat PTK7 orthologs, which explained the mechanism of PTK7 upregulation in colorectal cancer. NANOG-, SOX2-, and POU5F1 (OCT3/OCT4)-binding sites within intron 1 of the human SEMA6A gene were conserved in chimpanzee, rhesus monkey, mouse, and rat SEMA6A orthologs, which explained the mechanism of SEMA6A upregulation in undifferentiated ES cells. Most of non-canonical WNT or PCP signaling molecules, except PTK7 and SEMA6A, were not frequently expressed in undifferentiated human ES cells. Non-canonical WNT or PCP signaling pathway, activated to orchestrate gastrulation and neurulation, was relatively downregulated in undifferentiated ES cells derived from inner cell mass of blastocysts.
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PMID:Comparative integromics on non-canonical WNT or planar cell polarity signaling molecules: transcriptional mechanism of PTK7 in colorectal cancer and that of SEMA6A in undifferentiated ES cells. 1767 48

Carcinoma in situ (CIS) of the testis is the pre-invasive stage of type II testicular germ cell tumours (TGCTs) of adolescents and adults. These tumours are the most frequently diagnosed cancer in Caucasian adolescents and young adults. In dysgenetic gonads, the precursor of type II GCTs can be either CIS or a lesion known as gonadoblastoma (GB). CIS/GB originates from a primordial germ cell (PGC)/gonocyte, ie an embryonic cell. CIS can be cured by local low-dose irradiation, with limited side effects on hormonal function. Therefore, strategies for early diagnosis of CIS are essential. Various markers are informative to diagnose CIS in adult testis by immunohistochemistry, including c-KIT, PLAP, AP-2gamma, NANOG, and POU5F1 (OCT3/4). OCT3/4 is the most informative and consistent in presence and expression level, resulting in intense nuclear staining. In the case of maturational delay of germ cells, frequently present in gonads of individuals at risk for type II (T)GCTs, use of these markers can result in overdiagnosis of malignant germ cells. This demonstrates the need for a more specific diagnostic marker to distinguish malignant germ cells from germ cells showing maturation delay. Here we report the novel finding that immunohistochemical detection of stem cell factor (SCF), the c-KIT ligand, is informative in this context. This was demonstrated in over 400 cases of normal (fetal, neonatal, infantile, and adult) and pathological gonads, as well as TGCT-derived cell lines, specifically in cases of CIS and GB. Both membrane-bound and soluble SCF were expressed, suggestive of an autocrine loop. SCF immunohistochemistry can be a valuable diagnostic tool, in addition to OCT3/4, to screen for precursor lesions of TGCTs, especially in patients with germ cell maturation delay.
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PMID:Stem cell factor as a novel diagnostic marker for early malignant germ cells. 1856 70

Gonocytes are progenitor-type germ cells that arise from primordial germ cells and differentiate further into spermatogonia, thereby initiating spermatogenesis. In the present study, freshly isolated gonocytes were found to have either weak or no expression of pluripotency determining transcription factors, such as POU5F1, SOX2 and C-MYC. Interestingly, the expression of these transcription factors, as well as other vital transcription factors, such as NANOG, KLF4 and DAZL, were markedly upregulated in cultured cells. Cells in primary cultures expressed specific germ cell and pluripotency markers, such as lectin Dolichos biflorus agglutinin (DBA), KIT, ZBTB16, stage-specific embryonic antigen (SSEA-1), NANOG and POU5F1. Using a monoclonal antibody to specifically identify porcine germ cells, the stem cell potential of fresh and cultured cells was determined with a testis xenotransplantation assay. Colonised porcine germ cells were detected only in mouse testes that were either transplanted with fresh testicular cells or with cells from primary cultures. Interestingly, testes transplanted with cells from primary cultures showed colonisation of germ cells in the interstitial space, reflecting their tumourigenic nature. The formation of teratomas with tissues originating from the three germinal layers following the subcutaneous injection of cells into nude mice from primary cultures confirmed their multipotency. The results of the present study may provide useful information for the establishment of multipotent germ stem cell lines from neonatal pig testis.
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PMID:Multipotential ability of primitive germ cells from neonatal pig testis cultured in vitro. 1948 7

This study was designed to isolate, characterize, and culture human spermatogonia. Using immunohistochemistry on tubule sections, we localized GPR125 to the plasma membrane of a subset of the spermatogonia. Immunohistochemistry also showed that MAGEA4 was expressed in all spermatogonia (A(dark), A(pale), and type B) and possibly preleptotene spermatocytes. Notably, KIT was expressed in late spermatocytes and round spermatids, but apparently not in human spermatogonia. UCHL1 was found in the cytoplasm of spermatogonia, whereas POU5F1 was not detected in any of the human germ cells. GFRA1 and ITGA6 were localized to the plasma membrane of the spermatogonia. Next, we isolated GPR125-positive spermatogonia from adult human testes using a two-step enzymatic digestion followed by magnetic-activated cell sorting. The isolated GPR125-positive cells coexpressed GPR125, ITGA6, THY1, and GFRA1, and they could be cultured for short periods of time and exhibited a marked increase in cell numbers as shown by a proliferation assay. Immunocytochemistry of putative stem cell genes after 2 wk in culture revealed that the cells were maintained in an undifferentiated state. MAPK1/3 phosphorylation was increased after 2 wk of culture of the GPR125-positive spermatogonia compared to the freshly isolated cells. Taken together, these results indicate that human spermatogonia share some but not all phenotypes with spermatogonial stem cells (SSCs) and progenitors from other species. GPR125-positive spermatogonia are phenotypically putative human SSCs and retain an undifferentiated status in vitro. This study provides novel insights into the molecular characteristics, isolation, and culture of human SSCs and/or progenitors and suggests that the MAPK1/3 pathway is involved in their proliferation.
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PMID:Isolation, characterization, and culture of human spermatogonia. 1984 2

The objective was to examine the nuclear maturation of oocytes, embryonic development after parthenogenetic activation (PA) and somatic cell nuclear transfer (SCNT), and gene expression in SCNT embryos in pigs (Sus scrofa) when anthocyanin was added to oocytes during maturation and in vitro culture (IVC) of embryos. Immature oocytes were untreated or treated with 0.1 microg/mL anthocyanin during in vitro maturation (IVM). Next, PA and SCNT embryos were produced from oocytes and cultured in medium supplemented with or without 0.1 microg/mL anthocyanin for 7 d. Anthocyanin treatment during IVM did not improve the nuclear maturation of oocytes, but significantly increased intracellular glutathione (GSH) levels and reduced reactive oxygen species (ROS). Oocytes treated with anthocyanin during IVM had higher (P < 0.05) rates of blastocyst formation after PA (55.7 vs. 44.9 %) and SCNT (32.2 vs. 16.1%) compared to untreated oocytes. In PA and SCNT embryos, anthocyanin treatment during IVM or IVC significantly increased the intracellular GSH level, which led to the reduced ROS level. Somatic cell nuclear transfer embryos derived from anthocyanin-treated oocytes had increased (P < 0.05) expression of DNMT1, PCNA, FGFR2, and POU5F1 mRNA compared to control embryos. In conclusion, anthocyanin treatment during IVM improved developmental competence of SCNT embryos, most likely by increasing intracellular GSH synthesis, reducing ROS level, and stimulating nuclear reprogramming via increased transcription factor expression.
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PMID:Anthocyanin stimulates in vitro development of cloned pig embryos by increasing the intracellular glutathione level and inhibiting reactive oxygen species. 2053 99


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