HLA-DQA1 and HLA-DQB1 allele diversity and its extended haplotypes in Madeira Island (Portugal).

This study shows, for the first time, high-resolution allele frequencies of HLA-DQA1 loci in Madeira Island (Portugal) and allows us to better understand and refine present knowledge on DQB1 variation, with the identification of several alleles not previously reported in this population. Estimates on haplotype profile, involving HLA-A, HLA-B, HLA-DRB1, HLA-DQA1 and HLA-DQB1, are also reported.

Human leucocyte antigens class II allele and haplotype association with Type 1 Diabetes in Madeira Island (Portugal).

This study confirms for Madeira Island (Portugal) population the Type 1 Diabetes (T1D) susceptible and protective Human leucocyte antigens (HLA) markers previously reported in other populations and adds some local specificities. Among the strongest T1D HLA associations, stands out, as susceptible, the alleles DRB1*04:05 (OR = 7.3), DQB1*03:02 (OR = 6.1) and DQA1*03:03 (OR = 4.5), as well as the haplotypes DRB1*04:05-DQA1*03:03-DQB1*03:02 (OR = 100.9) and DRB1*04:04-DQA1*03:01-DQB1*03:02 (OR = 22.1), and DQB1*06:02 (OR = 0.07) and DRB1*15:01-DQA1*01:02-DQB1*06:02 (OR = 0.04) as protective. HLA-DQA1 positive for Arginine at position 52 (Arg52) (OR = 15.2) and HLA-DQB1 negative for Aspartic acid at the position 57 (Asp57) (OR = 9.0) alleles appear to be important genetic markers for T1D susceptibility, with higher odds ratio values than any single allele and than most of the haplotypes. Genotypes generated by the association of markers Arg52 DQA1 positive and Asp57 DQB1 negative increase T1D susceptibility much more than one would expected by a simple additive effect of those markers separately (OR = 26.9). This study also confirms an increased risk for DRB1*04/DRB1*03 heterozygote genotypes (OR = 16.8) and also a DRB1*04-DQA1*03:01-DQB1*03:02 haplotype susceptibility dependent on the DRB1*04 allele (DRB1*04:01, OR = 7.9; DRB1*04:02, OR = 3.2; DRB1*04:04, OR = 22.1).

[Clinical aspects and genetics of proteasome-associated autoinflammatory syndromes (PRAAS)]. / Klinik und Genetik bei Proteasomen-assoziierten autoinflammatorischen Syndromen (PRAAS).

Functional disorders of the proteasome can have a severe impact on the innate immune system. Characterized by an autosomal recessive mode of inheritance, this novel type of interferonopathy is considered to be a spectrum of diseases of proteasome-associated autoinflammatory syndromes (PRAAS). Accumulation of ubiquitinated proteins and the induction of type I interferon (IFN) genes seem to play a role in the pathogenesis. The typical clinical manifestations are lipodystrophy, skin, joint and muscle involvement accompanied by a remarkable variability of other associated symptoms. This article provides an overview on currently known molecular alterations as well as clinical similarities and differences of PRAAS. Furthermore, the reported effects of the immunosuppressive therapy approaches used so far are summarized.

Association of ADAMTS7 gene polymorphism with cardiovascular survival in coronary artery disease.

Recent genetic studies have revealed an association between polymorphisms at the ADAMTS7 gene locus and coronary artery disease (CAD) risk. Functional studies have shown that a CAD-associated polymorphism (rs3825807) affects ADAMTS7 maturation and vascular smooth muscular cell (VSMC) migration. Here, we tested whether ADAMTS7 (A/G) SNP is associated with cardiovascular (CV) survival in patients with established CAD. A cohort of 1,128 patients with angiographic proven CAD, who were followed up prospectively for a mean follow-up period of 63 (range 6-182) mo, were genotyped for rs3825807 A/G. Survival statistics (Cox regression) compared heterozygous (AG) and wild-type (AA) with the reference homozygous GG. Kaplan-Meier (K-M) survival curves were performed according to ADAMTS7 genotypes for CV mortality. Results showed that 47.3% of patients were heterozygous (AG), 36.5% were homozygous for the wild-type allele (AA) and only 16.2% were homozygous for the GG genotype. During the follow-up period, 109 (9.7%) patients died, 77 (6.8%) of CV causes. Survival analysis showed that AA genotype was an independent risk factor for CV mortality compared with reference genotype GG (HR = 2.7, P = 0.025). At the end of follow-up, the estimated survival probability (K-M) was 89.8% for GG genotype, 82.2% for AG and 72.3% for AA genotype (P = 0.039). Carriage of the mutant G allele of the ADAMTS7 gene was associated with improved CV survival in patients with documented CAD. The native overfunctional ADAMTS7 allele (A) may accelerate VSMC migration and lead to neointimal thickening, atherosclerosis progression and acute plaque events. ADAMTS7 gene should be further explored in CAD for risk prediction, mechanistic and therapeutic goals.

Effects of pioglitazone versus glimepiride exposure on hepatocellular fat content in type 2 diabetes.

AIMS: Thiazoledinediones decrease blood glucose by their insulin-sensitizing properties. Here, we examined whether pioglitazone plus nateglinide (PIO) interferes with hepatocellular lipid (HCL) content and/or improves insulin sensitivity in well-controlled non-obese patients with type 2 diabetes mellitus (T2DM). METHODS: Sixteen patients [body mass index (BMI): 28 ± 1 kg/m(2) ; HbA1c: 7.1 ± 0.6%] were studied in a randomized, double-blind, 12-week parallel group trial, whereas matched healthy humans [non-diabetic control subjects (CON), BMI: 26 ± 1 kg/m(2)] were studied once. Treatment with pioglitazone (30 mg/day) plus nateglinide (PIO arm) to control for glimepiride-induced insulin secretion was compared to treatment with glimepiride (2 mg/day) plus placebo (GLI arm). Multinuclei magnetic resonance spectroscopy (MRS) was combined with pancreatic normoglycaemic-two-step-insulin clamps and stable isotopes to assess glucose turnover, glucose transport/phosphorylation, HCL and intramyocellular lipid (IMCL) contents, non-esterified fatty acids (NEFA) and adipokines. RESULTS: At baseline, HCL was approximately 5.6-fold higher in T2DM (p < 0.05 vs. CON). This was paralleled by approximately doubled leptin : adiponectin ratios (p < 0.05). HCL decreased by approximately 39% (p < 0.05) after PIO and only tended to decrease after GLI (p = 0.12). Treatment with PIO did not affect leptin : adiponectin ratios, but slightly improved (p < 0.05) insulin-mediated NEFA suppression, which related to lower HCL. PIO further prevented the insulin-induced increase in IMCL content of soleus and tibialis anterior muscles. Peripheral and hepatic insulin sensitivity, glucose transport and glycaemic control did not change in both groups. CONCLUSION: Short-term, low-dose thiazolidendione treatment improves insulin sensitivity of lipolysis and HCL, without affecting muscle and liver insulin sensitivity. It appears that metabolic PIO action in T2DM is primarily mediated via a decline in HCL associated with greater sensitivity of lipolysis to insulin.

DNA methyltransferase Dnmt1 associates with histone deacetylase activity.

The DNA methyltransferase Dnmt1 is responsible for cytosine methylation in mammals and has a role in gene silencing. DNA methylation represses genes partly by recruitment of the methyl-CpG-binding protein MeCP2, which in turn recruits a histone deacetylase activity. Here we show that Dnmt1 is itself associated with histone deacetylase activity in vivo. Consistent with this association, we find that one of the known histone deacetylases, HDAC1, has the ability to bind Dnmt1 and can purify methyltransferase activity from nuclear extracts. We have identified a transcriptional repression domain in Dnmt1 that functions, at least partly, by recruiting histone deacetylase activity and shows homology to the repressor domain of the trithorax-related protein HRX (also known as MLL and ALL-1). Our data show a more direct connection between DNA methylation and histone deacetylation than was previously considered. We suggest that the process of DNA methylation, mediated by Dnmt1, may depend on or generate an altered chromatin state via histone deacetylase activity.

Effective Dose Measurements of the Latest-Generation Angiographic System in Patients with Acute Stroke: A Comparison with the Newest Multidetector CT Generation.

BACKGROUND AND PURPOSE: Patients with acute ischemic stroke are increasingly triaged with one-stop management approaches, resulting in baseline imaging with a flat detector CT scanner. This study aimed to estimate the effective dose to a patient of a novel cervical and intracranial flat detector CT angiography and a flat detector CT perfusion protocol and to compare it with the effective dose of analogous multidetector row CT protocols. MATERIALS AND METHODS: We estimated the effective dose to the patient according to the International Commission on Radiological Protection 103 using an anthropomorphic phantom with metal oxide semiconductor field effect transistor dosimeters. Placement was according to the organ map provided by the phantom manufacturer. We used 100 measurement points within the phantom, and 18 metal oxide semiconductor field effect transistor dosimeters were placed on the surface of the phantom. All protocols followed the manufacturer's specifications, and patient positioning and collimation were performed as in routine clinical practice. Measurements were obtained on the latest-generation angiography and multidetector row CT systems with identical placement of the metal oxide semiconductor field effect transistor dosimeters. RESULTS: The estimated effective doses of the investigated perfusion protocols were 4.52 mSv (flat detector CT perfusion without collimation), 2.88 mSv (flat detector CT perfusion with collimation), and 2.17 mSv (multidetector row CT perfusion). A novel protocol called portrait flat detector CT angiography that has a z-axis coverage area comparable with that of multidetector row CT angiography had an estimated effective dose of 0.91 mSv, while the dose from multidetector row CT was 1.35 mSv. CONCLUSIONS: The estimated effective dose to the patient for flat detector CT perfusion and angiography on a modern biplane angiography system does not deviate substantially from that of analogous multidetector row CT protocols.

Impaired insulin stimulation of muscular ATP production in patients with type 1 diabetes.

OBJECTIVE: in type 2 diabetic patients and their first-degree relatives, insulin resistance (IR) is associated with impairment of insulin-stimulated myocellular glucose-6-phosphate (g6p) and unidirectional flux through ATP synthase (fATP), suggesting the presence of inherited abnormal mitochondrial oxidative fitness. We hypothesized that patients with long-standing type 1 diabetes may also exhibit insulin resistance as well as lower fATP. DESIGN: this single-centre trial was registered at ClinicalTrials.gov (NCT00481598). SUBJECTS: we included eight nonobese type 1 diabetic patients (mean diabetes duration: 17 years) with near-target glycaemic control [haemoglobin A1c (HbA1c): 6.8 ± 0.4%] during treatment with continuous subcutaneous insulin infusion pumps and eight healthy volunteers (HbA1c: 5.4 ± 0.2%) of comparable age, body mass and level of physical activity. OUTCOME MEASURES: myocellular fATP, g6p and intramyocellular lipid content (IMCL) were measured with (1) H/(31) P magnetic resonance spectroscopy during fasting and hyperinsulinaemic-euglycaemic clamp tests. RESULTS: fasting fATP, g6p and IMCL did not differ between groups. During stimulation by insulin, type 1 diabetic patients exhibited approximately 50% (P < 0.001) lower whole-body glucose disposal along with approximately 42% (P = 0.003) lower intramyocellular g6p and approximately25% (P = 0.024) lower fATP. Insulin-stimulated fATP correlated positively with whole-body insulin sensitivity (R = 0.706, P = 0.002) and negatively with HbA1c (R = -0.675, P = 0.004). CONCLUSIONS: despite documented near-target glycaemic control for 1 year, nonobese patients with long-standing type 1 diabetes can exhibit insulin resistance. This associates with lower insulin-stimulated flux through muscular ATP synthase which could result from glucose toxicity.

Acute elevation of plasma lipids does not affect ATP synthesis in human skeletal muscle.

Prolonged elevation of plasma triglycerides and free fatty acids (FFA) reduces insulin-stimulated glucose disposal and myocellular flux through ATP synthase (fATPase). However, the early effects of lipids per se on fATPase are as yet unclear. Thus, this study examined glucose disposal and fATPase during 3 h of FFA elevation in the presence of low plasma insulinemia. Euglycemic pancreatic clamps with low-dose insulin supplementation (6 mU.m body surface area(-2).min(-1)) were performed in eight healthy men with (LIP) or without (CON) lipid infusion to measure whole body glucose disposal. (31)P/(1)H magnetic resonance spectroscopy of calf muscle was applied to quantify fATPase and concentrations of glucose 6-phosphate (G6P), inorganic phosphate (P(i)), phosphocreatine (PCr), ADP, pH, and IMCL before and during the clamps. Lipid infusion increased plasma FFA approximately twofold and decreased glucose disposal by approximately 50% (110-180 min: LIP 0.87 +/- 0.45 vs. CON 1.75 +/- 0.42 mg.kg(-1).min(-1), P = 0.002; means +/- SD). Intramyocellular G6P tended to rise only under control conditions, whereas PCr, ADP, pH, and IMCL remained unchanged from fasting in LIP and CON. Although P(i) concentrations increased by approximately 18%, fATPase remained unchanged from fasting during the clamps (LIP 10.2 +/- 2.2 vs. CON 10.5 +/- 2.6 micromol.g muscle(-1).min(-1), P = not significant). We conclude that 3 h of lipid elevation fail to affect ATP synthesis despite marked reduction of whole body glucose uptake. This suggests that lipid-induced insulin resistance results primarily from mechanisms decreasing glucose uptake rather than from direct interference of fatty acid metabolites with mitochondrial function.

Endovascular Thrombectomy of Calcified Emboli in Acute Ischemic Stroke: A Multicenter Study.

BACKGROUND AND PURPOSE: Large intracranial vessel occlusion due to calcified emboli is a rare cause of major stroke. We assessed the prevalence, imaging appearance, the effectiveness of mechanical thrombectomy, and clinical outcome of patients with large-vessel occlusion due to calcified emboli. MATERIALS AND METHODS: We performed a retrospective analysis of clinical and procedural data of consecutive patients who underwent mechanical thrombectomy due to calcified emboli in 7 European stroke centers. RESULTS: We screened 2969 patients, and 40 patients matched the inclusion criteria, accounting for a prevalence of 1.3%. The mean maximal density of the thrombus was 327 HU (range, 150-1200 HU), and the mean thrombus length was 9.2 mm (range, 4-20 mm). Four patients had multiple calcified emboli, and 2 patients had an embolic event during an endovascular intervention. A modified TICI score of ≥2b was achieved in 57.5% (23/40), with minimal-to-no reperfusion (modified TICI 0-1) in 32.5% (13/40) and incomplete reperfusion (modified TICI 2a) in 10% (4/40). Excellent outcome (mRS 0-1) was achieved in only 20.6%, functional independence (mRS 0-2) in 26.5% and 90-day mortality was 55.9%. CONCLUSIONS: Acute ischemic stroke with large-vessel occlusion due to calcified emboli is a rare entity in patients undergoing thrombectomy, with considerably worse angiographic outcome and a higher mortality compared with patients with noncalcified thrombi. Good functional recovery at 3 months can still be achieved in about a quarter of patients.

Retinoblastoma protein meets chromatin.

The retinoblastoma (RB) protein exerts its tumour-suppressor function by repressing the transcription of cellular genes required for DNA replication and cell division. Recent investigations into the mechanism of RB repression have revealed that RB can regulate transcription by effecting changes in chromatin structure. These findings point towards a link between chromatin regulation and cancer.

One-Stop Management with Perfusion for Transfer Patients with Stroke due to a Large-Vessel Occlusion: Feasibility and Effects on In-Hospital Times.

BACKGROUND AND PURPOSE: In-hospital time delays lead to a relevant deterioration of neurologic outcomes in patients with stroke with large-vessel occlusions. At the moment, CT perfusion is relevant in the triage of late-window patients with stroke. We conducted this study to determine whether one-stop management with perfusion is feasible and leads to a reduction of in-hospital times. MATERIALS AND METHODS: In this observational study, we report the first 15 consecutive transfer patients with stroke with externally confirmed large-vessel occlusions who underwent flat panel detector CT perfusion and thrombectomy in the same room. Preinterventional imaging consisted of noncontrast flat panel detector CT and flat panel detector CT perfusion, acquired with a biplane angiography system. The flat panel detector CT perfusion was used to reconstruct a flat panel detector CT angiography to confirm the large-vessel occlusions. After confirmation of the large-vessel occlusion, the patient underwent mechanical thrombectomy. We recorded time metrics and safety parameters prospectively and compared them with those of transfer patients whom we treated before the introduction of one-stop management with perfusion. RESULTS: Fifteen transfer patients underwent flat panel detector CT perfusion and were treated with mechanical thrombectomy from June 2017 to January 2019. The median time from symptom onset to admission was 241 minutes. Median door-to-groin time was 24 minutes. Compared with 23 transfer patients imaged with multidetector CT, it was reduced significantly (24 minutes; 95% CI, 19-37 minutes, versus 53 minutes; 95% CI, 44-66 minutes; P < .001). Safety parameters were comparable between groups. CONCLUSIONS: In this small series, one-stop management with perfusion led to a significant reduction of in-hospital times compared with our previous workflow.

HLA-A polymorphisms in four ethnic groups from Guinea-Bissau (West Africa) inferred from sequence-based typing.

Human leukocyte antigen (HLA)-A locus polymorphisms were examined at high-resolution level, using sequence-based typing, in the four most representative Guinea-Bissau (Northwest Africa) ethnic groups: Balanta, Bijagós, Fula and Papel. Despite the Fula group having significant differences when compared with the other three ethnic groups, all four groups most likely received a genetic input from non sub-Saharans. The Bijagós and Papel groups showed similarities to neighboring populations from Mali and Senegal. The Balanta, despite their oral tradition of an East Africa origin, show affinities to Cameroon populations, highly influenced by Bantu migrations. These results are congruent with historical sources and other genetic studies that support the finding that the Guinea-Bissau genetic pool was influenced by several migrations from North Africa, Sahara and East Africa.

Novel familial mutation of LRP5 causing high bone mass: Genetic analysis, clinical presentation, and characterization of bone matrix mineralization.

The Wnt signalling pathway is a critical regulator of bone mass and quality. Several heterozygous mutations in the LRP5 gene, a Wnt co-receptor, causing high bone mass (LRP5-HBM) have been described to date. The pathogenic mechanism is thought to be a gain-of-function caused by impaired inhibition of the canonical Wnt signalling pathway, thereby leading to increased bone formation. We report the cases of two affected family members, a 53-year-old mother and her 23-year-old daughter, with high bone mass (T-scores mother: lumbar spine 11.4, femoral neck 10.5; T-scores daughter: lumbar spine 5.4, femoral neck 8.7), increased calvarial thickness, and thickened cortices of the long bones but no history of fractures. Whereas the mother did not show any indications of the mutation, the daughter suffered from congenital hearing impairment resulting in cochlear implantation, recurrent facial palsy, and migraine. In addition, she had stenosis of the foramen magnum. In both individuals, we detected a novel heterozygous duplication of six basepairs in the LRP5 gene, resulting in an insertion of two amino acids, very likely associated with a gain-of-function. When the daughter had part of the occipital bone surgically removed, the bone sample was used for the visualization of bone lamellar structure and bone cells as well as the measurement of bone mineralization density distribution (BMDD). The bone sample revealed two distinctly different regions: an intra-cortical region with osteonal remodeling, typical osteonal lamellar orientation, associated with relatively higher heterogeneity of bone matrix mineralization, and another periosteal region devoid of bone remodeling, with parallel bone lamellae and lower heterogeneity of mineralization. In conclusion, we present data on bone tissue and material level from an LRP5-HBM patient with a novel mutation in the LRP5 gene. Our findings indicate normal morphology of osteoclasts and osteoblasts as well as normal mineralization in skull bone in LRP5-HBM.

The carboxy-terminal transactivation domain of Oct-4 acquires cell specificity through the POU domain.

The POU transcription factor Oct-4 is expressed in totipotent and pluripotent cells of the early mouse embryo and the germ cell lineage. Transactivation capacities of regions flanking the DNA binding domain of Oct-4 were analyzed in undifferentiated and differentiated cell lines. The amino- and carboxy-terminal regions (N domain and C domain) fused to the Gal4 DNA binding domain both functioned as transactivation domains in all cell lines tested. However, the C domain failed to activate transcription in some cell lines in the context of the native protein. The underlying regulatory mechanism appears to involve the POU domain of Oct-4 and can discriminate between different POU domains, since constructs in which the C domain was instead fused to the POU domain of Pit-1 were again equally active in all cell lines. These results indicate that the C domain is subject to cell-type-specific regulation mediated by the Oct-4 POU domain. Phosphopeptide analysis revealed that the cell-type-specific difference of C-domain activity correlates with a difference in Oct-4 phosphorylation status. Since Oct-4 is expressed in a variety of distinct cell types during murine embryogenesis, these results suggest an additional regulatory mechanism for determining Oct-4 function in rapidly changing cell types during development.

Temporal recruitment of the mSin3A-histone deacetylase corepressor complex to the ETS domain transcription factor Elk-1.

The transcriptional status of eukaryotic genes is determined by a balance between activation and repression mechanisms. The nuclear hormone receptors represent classical examples of transcription factors that can regulate this balance by recruiting corepressor and coactivator complexes in a ligand-dependent manner. Here, we demonstrate that the equilibrium between activation and repression via a single transcription factor, Elk-1, is altered following activation of the Erk mitogen-activated protein kinase cascade. In addition to its C-terminal transcriptional activation domain, Elk-1 contains an N-terminal transcriptional repression domain that can recruit the mSin3A-histone deacetylase 1 corepressor complex. Recruitment of this corepressor is enhanced in response to activation of the Erk pathway in vivo, and this recruitment correlates kinetically with the shutoff of one of its target promoters, c-fos. Elk-1 therefore undergoes temporal activator-repressor switching and contributes to both the activation and repression of target genes following growth factor stimulation.

Synergism with germ line transcription factor Oct-4: viral oncoproteins share the ability to mimic a stem cell-specific activity.

Activation of transcription by Oct-4 from remote binding sites requires a cofactor that is restricted to embryonal stem cells. The adenovirus E1A protein can mimic the activity of this stem cell-specific factor and stimulates Oct-4 activity in differentiated cells. Here we characterize the Oct-4-E1A interaction and show that the E1A 289R protein harbors two independent Oct-4 binding sites, both of which specifically interact with the POU domain of Oct-4. Furthermore, we demonstrate that, like E1A, the human papillomavirus E7 oncoprotein also specifically binds to the Oct-4 POU domain. E7 and Oct-4 can form a complex both in vitro and in vivo. Expression of E7 in differentiated cells stimulates Oct-4-mediated transactivation from distal binding sites. Moreover, Oct-4, but not other Oct factors, is active when expressed in cells transformed by human papillomavirus. Our results suggest that different viruses have evolved oncoproteins that share the ability to target Oct-4 and to mimic a stem cell-specific activity.

Transcriptional repression by the insulator protein CTCF involves histone deacetylases.

The highly conserved zinc-finger protein, CTCF, is a candidate tumor suppressor protein that binds to highly divergent DNA sequences. CTCF has been connected to multiple functions in chromatin organization and gene regulation including chromatin insulator activity and transcriptional enhancement and silencing. Here we show that CTCF harbors several autonomous repression domains. One of these domains, the zinc-finger cluster, silences transcription in all cell types tested and binds directly to the co-repressor SIN3A. Two distinct regions of SIN3A, the PAH3 domain and the extreme C-terminal region, bind independently to this zinc-finger cluster. Analysis of nuclear extract from HeLa cells revealed that CTCF is also capable of retaining functional histone deacetylase activity. Furthermore, the ability of regions of CTCF to retain deacetylase activity correlates with the ability to bind to SIN3A and to repress gene activity. We suggest that CTCF driven repression is mediated in part by the recruitment of histone deacetylase activity by SIN3A.

Tumour suppressors--a fly's perspective.

For a century, the little fruitfly Drosophila melanogaster has taught generations of geneticists about how genes control the development of a multicellular organism. More recently, Drosophila has begun to contribute more directly towards our understanding of human disease [Bernards A, Hariharan IK. Of flies and men-studying human disease in Drosophila. Curr Opin Genet Dev 2001, 11, 274-278]. It is capable of doing this because it shares many disease-related genes with us. For example, the Drosophila genome sequencing project has revealed that two thirds of the genes implicated in human cancers have a counterpart in the fly genome [Adams MD, Celniker SE, Holt RA, et al. The genome sequence of Drosophila melanogaster. Science 2000, 287, 2185-2195, Fortini ME, Skupski MP, Boguski MS, Hariharan IK. A survey of human disease gene counterparts in the Drosophila genome. J Cell Biol 2000, 150, F23-30]. In particular, the fly has homologues of the Retinoblastoma protein (pRb) and of p53, two prototypical tumour suppressors which are inactivated in the majority of human tumours. Here, we will compare the fly's tumour suppressors with their human counterparts and we will review recent advances in our understanding of how these factors function in the fly.

Oct-4: more than just a POUerful marker of the mammalian germline?

Mammals lack visible cytoplasmic components in the oocyte that could account for 'germline determinants' as identified in various non-mammalian species. Actually, mammals might not define the germline autonomously by localized 'germline determinants' but conditionally depending on the position of cells within the embryo. The Oct-4 gene encodes a transcription factor that is specifically expressed in the toti- and pluripotential stem cells of the mouse embryo and so far has only been found in mammalian species. Oct-4-expressing embryonal cell retain the capacity to differentiate along multiple lineages and they have been suggested to be part of a 'totipotent germline cycle' that links one generation to the next.