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Berlin Brandenburg

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  • 1
    Dissertation
    Dissertation
    University College London (University of London)
    Language: English
    Description: Hesx1 is a homeobox transcriptional repressor that is required for correct specification and development of the forebrain and pituitary gland. Moreover, inactivating mutations in humans have been previously linked with Septo Optic Dysplasia (SOD), a congenital condition causative of hypopituitarism and...
    Source: The British Library
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences, 07/12/2011, Vol.108(28), pp.11482-11487
    Description: Wingless (Wnt)/[beta]-catenin signaling plays an essential role during normal development, is a critical regulator of stem cells, and has been associated with cancer in many tissues. Here we demonstrate that genetic expression of a degradation-resistant mutant form of [beta]-catenin in early Rathke's pouch (RP) progenitors leads to pituitary hyperplasia and severe disruption of the pituitary-specific transcription factor 1-lineage differentiation resulting in extreme growth retardation and hypopituitarism. Mutant mice mostly die perinatally, but those that survive weaning develop lethal pituitary tumors, which closely resemble human adamantinomatous craniopharyngioma, an epithelial tumor associated with mutations in the human [beta]-catenin gene. The tumorigenic effect of mutant [beta]-catenin is observed only when expressed in undifferentiated RP progenitors, but tumors do not form when committed or differentiated cells are targeted to express this protein. Analysis of affected pituitaries indicates that expression of mutant [beta]-catenin leads to a significant increase in the total numbers of pituitary progenitor/ stem cells as well as in their proliferation potential. Our findings provide insights into the role of the Wnt pathway in normal pituitary development and demonstrate a causative role for mutated [beta]-catenin in an undifferentiated RP progenitor in the genesis of murine and human craniopharyngioma. doi/10.1073/pnas.1101553108
    Keywords: Stem Cells -- Analysis ; Pituitary Tumors -- Research ; Pituitary Tumors -- Analysis ; Gene Expression -- Analysis;
    ISSN: 0027-8424
    E-ISSN: 1091-6490
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  • 3
    Language: English
    In: Development, 11/15/2011, Vol.138(22), pp.4931-4942
    Description: The Wnt/β-catenin pathway plays an essential role during regionalisation of the vertebrate neural plate and its inhibition in the most anterior neural ectoderm is required for normal forebrain development. Hesx1 is a conserved vertebrate-specific transcription factor that is required for forebrain development in Xenopus, mice and humans. Mouse embryos deficient for Hesx1 exhibit a variable degree of forebrain defects, but the molecular mechanisms underlying these defects are not fully understood. Here, we show that injection of a hesx1 morpholino into a 'sensitised' zygotic headless (tcf3) mutant background leads to severe forebrain and eye defects, suggesting an interaction between Hesx1 and the Wnt pathway during zebrafish forebrain development. Consistent with a requirement for Wnt signalling repression, we highlight a synergistic gene dosage-dependent interaction between Hesx1 and Tcf3, a transcriptional repressor of Wnt target genes, to maintain anterior forebrain identity during mouse embryogenesis. In addition, we reveal that Tcf3 is essential within the neural ectoderm to maintain anterior character and that its interaction with Hesx1 ensures the repression of Wnt targets in the developing forebrain. By employing a conditional loss-of-function approach in mouse, we demonstrate that deletion of β-catenin, and concomitant reduction of Wnt signalling in the developing anterior forebrain of Hesx1-deficient embryos, leads to a significant rescue of the forebrain defects. Finally, transcriptional profiling of anterior forebrain precursors from mouse embryos expressing eGFP from the Hesx1 locus provides molecular evidence supporting a novel function of Hesx1 in mediating repression of Wnt/β-catenin target activation in the developing forebrain.
    Keywords: Medicine ; Biology ; Zoology;
    ISSN: 0950-1991
    E-ISSN: 1477-9129
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences, 11/03/2009, Vol.106(44), pp.18728-18733
    Description: The retinal pigment epithelium (RPE) plays a critical role in the maintenance of the outer retina. RPE cell death or dysfunction drives the pathophysiology of many retinal diseases, but the physiological response of the retina to RPE cell loss is poorly understood, mainly because of the absence of suitable experimental models. Here, we generated a transgenic mouse in which an inducible Cre recombinase is expressed exclusively in the RPE under the control of the mono-carboxylate transporter 3 gene promoter ([RPE.sup.CreER]). This was crossed with a transgenic mouse harboring a diphtheria toxin A (DTA) chain gene rendered transcriptionally silent by a floxed stop sequence. We show that activation of DTA in the double transgenic mouse ([RPE.sup.CreER]/DTA) led to 60-80% RPE cell death, with surviving cells maintaining the integrity of the monolayer by increasing their size. Despite the apparent morphological normality of the enlarged RPE cells in the RPECreER/DTA mice, functional analysis revealed significant deficits on electroretinography, and retinal histopathology showed regions of photoreceptor rosetting and degeneration although with retention of a normal vascular network. Our study reveals that whilst the RPE monolayer has a remarkable intrinsic capacity to cope with cellular attrition, specific aspects of RPE multifunctionality essential for photoreceptor survival are compromised. The [RPE.sup.CreER]/DTA mouse offers advantages over models that employ chemical or mechanical strategies to kill RPE cells, and should be useful for the development and evaluation of RPE-based therapies, such as stem cell transplantation. cell death | pigment | retina www.pnas.org/cgi/doi/ 10.1073/pnas.0902593106
    Keywords: Cell Death -- Research ; Epithelium -- Properties ; Photoreceptors -- Properties ; Visual Pigments -- Physiological Aspects;
    ISSN: 0027-8424
    E-ISSN: 1091-6490
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  • 5
    Language: English
    In: Science, 08/01/2008, Vol.321(5889), pp.702-705
    Description: Peripheral pain pathways are activated by a range of stimuli. We used diphtheria toxin to kill all mouse postmitotic sensory neurons expressing the sodium channel $\text{Na}_{\text{v}}1.8$ . Mice showed normal motor activity and low-threshold mechanical and acute noxious heat responses but did not respond to noxious mechanical pressure or cold. They also showed a loss of enhanced pain responses and spontaneous pain behavior upon treatment with inflammatory insults. In contrast, nerve injury led to heightened pain sensitivity to thermal and mechanical stimuli indistinguishable from that seen with normal littermates. Pain behavior correlates well with central input from sensory neurons measured electrophysiologically in vivo. These data demonstrate that $\text{Na}_{\text{v}}1.8$ -expressing neurons are essential for mechanical, cold, and inflammatory pain but not for neuropathic pain or heat sensing.
    Keywords: Health sciences -- Medical conditions -- Symptoms ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Cytology ; Health sciences -- Medical conditions -- Diseases ; Behavioral sciences -- Psychology -- Cognitive psychology ; Biological sciences -- Biology -- Zoology ; Biological sciences -- Biology -- Anatomy ; Biological sciences -- Biology -- Anatomy ; Biological sciences -- Biology -- Neuroscience ; Biological sciences -- Biochemistry -- Biomolecules ; Health sciences -- Medical conditions -- Symptoms ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Cytology ; Health sciences -- Medical conditions -- Diseases ; Behavioral sciences -- Psychology -- Cognitive psychology ; Biological sciences -- Biology -- Zoology ; Biological sciences -- Biology -- Anatomy ; Biological sciences -- Biology -- Anatomy ; Biological sciences -- Biology -- Neuroscience ; Biological sciences -- Biochemistry -- Biomolecules;
    ISSN: 0036-8075
    E-ISSN: 1095-9203
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  • 6
    In: Endocrine Abstracts, 03/01/2014
    ISSN: Endocrine Abstracts
    E-ISSN: 1479-6848
    Source: CrossRef
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  • 7
    Language: English
    In: Development, 05/16/2007, Vol.134(12), pp.2349-2358
    Description: It has been proposed that the mammalian adrenal cortex and gonad are derived from the same primordium present during early urogenital development. Molecular pathways involved in the differentiation of the adrenal cortex from the adrenogonadal primordium (AGP) have yet to be determined. Here we show in mice that the transcription co-factor Cited2 is required for the specification of the adrenal cortex from the AGP. We present genetic and molecular evidence demonstrating that Cited2 interacts with the transcription factor Wt1 to stimulate expression of the nuclear hormone receptor Sf-1 (Nr5a1) in the AGP prior to the separation between gonad and adrenal cortex. We show a direct correlation between the expression levels of Sf-1 in the AGP and the defects in adrenal development found in mice with different Cited2 and Wt1 mutant backgrounds. Analysis of embryos heterozygous for mutations in both Sf-1 and Cited2 confirmed that these genes act in the same pathway during adrenal development. Our studies reveal a regulatory mechanism in which Cited2 acts as a Wt1 co-factor to increase, at a critical time in embryogenesis, the levels of the essential transcription factor Sf-1 in the AGP above the threshold required to determine adrenal development. These results highlight the importance of transcription factor dosage in organogenesis and the role of transcription co-factors such as Cited2 in determining the levels of these factors.
    Keywords: Gene Dosage ; Adrenal Glands -- Embryology ; DNA-Binding Proteins -- Metabolism ; Homeodomain Proteins -- Metabolism ; Receptors, Cytoplasmic and Nuclear -- Metabolism ; Repressor Proteins -- Metabolism ; Trans-Activators -- Metabolism ; Transcription Factors -- Metabolism ; Wt1 Proteins -- Metabolism;
    ISSN: 0950-1991
    E-ISSN: 1477-9129
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  • 8
    Language: English
    In: Human Molecular Genetics, 08/01/2010, Vol.19(15), pp.3103-3103
    Keywords: Medicine ; Biology;
    ISSN: 0964-6906
    E-ISSN: 1460-2083
    Source: Oxford University Press (via CrossRef)
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  • 9
    Dissertation
    Dissertation
    University College London (University of London)
    Description: Mouse studies have demonstrated the necessity of sonic hedgehog (SHH) for normal proliferation of Rathke’s pouch (RP) precursors. However, the possible function of SHH in pituitary cell specification remains to be assessed. Additionally, evidence suggests that SHH may be relevant in human adamantinomatous craniopharyngioma (ACP), a benign, but aggressive childhood pituitary tumour associated with high morbidity. In this study I aim to determine the function of SHH during normal pituitary development and in human ACP. Specifically, I aim to test whether SHH is relevant for cell specification during pituitary development and whether it is pathogenic in ACP. In this study I show that conditional deletion of Shh in the Hesx1-cell lineage arrests RP development with complete loss of pituitary tissue by 12.5 dpc. Molecular analyses indicate that Shh is not only required for proliferation, but also, for normal specification of RP precursors. Without hypothalamic SHH signalling, critical RP progenitor markers are not expressed, leading to a change in cell fate. The results in this study also show that SHH is expressed in human ACP tumour samples, along with the direct targets, Gli1 and Ptch1, indicating pathway activation within these tumours. Conditional deletion of Shh in a murine ACP model revealed no difference in tumour formation/progression. However, SHH is still detected in non-targeted cells. Lastly, a pre-clinical trial using a small molecule inhibitor of the SHH pathway (Vismodegib, Roche) was performed. Results from the pre-clinical trial suggest that SHH may have a protective role in ACP pathogenesis. SHH pathway inhibition lead to a decrease in survival and an increase in the rate of tumourigenesis evidenced by an increase in proliferation and cells with clonogenic potential. In 4 conclusion, we reveal a novel role for SHH in the specification of RP precursors, demonstrate the activation of the pathway in human ACP and reveal the effects of SHH pathway inhibition on ACP tumourigenesis.
    Keywords: 618.92
    Source: Networked Digital Library of Theses and Dissertations
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  • 10
    Dissertation
    Dissertation
    University College London (University of London)
    Language: English
    Description: Mouse studies have demonstrated the necessity of sonic hedgehog (SHH) for normal proliferation of Rathke’s pouch (RP) precursors. However, the possible function of SHH in pituitary cell specification remains to be assessed. Additionally, evidence suggests that SHH may be relevant in human adamantinomatous...
    Keywords: 618.92
    Source: The British Library
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