120 results on '"Gaston-Massuet, Carles"'
Search Results
2. Correction: RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas
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Garcia-Rendueles, Angela R., Chenlo, Miguel, Oroz-Gonjar, Fernando, Solomou, Antonia, Mistry, Anisha, Barry, Sayka, Gaston-Massuet, Carles, Garcia-Lavandeira, Montserrat, Perez-Romero, Sihara, Suarez-Fariña, Maria, Pradilla-Dieste, Alberto, Dieguez, Carlos, Mehlen, Patrick, Korbonits, Márta, and Alvarez, Clara V.
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- 2023
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3. Phosphorylation of β-catenin at Serine552 correlates with invasion and recurrence of non-functioning pituitary neuroendocrine tumours
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Rai, Ashutosh, Yelamanchi, Soujanya D., Radotra, Bishan D., Gupta, Sunil K., Mukherjee, Kanchan K., Tripathi, Manjul, Chhabra, Rajesh, Ahuja, Chirag K., Kumar, Narendra, Pandey, Akhilesh, Korbonits, Márta, Dutta, Pinaki, and Gaston-Massuet, Carles
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- 2022
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4. RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas
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Garcia-Rendueles, Angela R., Chenlo, Miguel, Oroz-Gonjar, Fernando, Solomou, Antonia, Mistry, Anisha, Barry, Sayka, Gaston-Massuet, Carles, Garcia-Lavandeira, Montserrat, Perez-Romero, Sihara, Suarez-Fariña, Maria, Pradilla-Dieste, Alberto, Dieguez, Carlos, Mehlen, Patrick, Korbonits, Márta, and Alvarez, Clara V.
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- 2021
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5. Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans
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Gualtieri, Angelica, Kyprianou, Nikolina, Gregory, Louise C., Vignola, Maria Lillina, Nicholson, James G., Tan, Rachael, Inoue, Shin-ichi, Scagliotti, Valeria, Casado, Pedro, Blackburn, James, Abollo-Jimenez, Fernando, Marinelli, Eugenia, Besser, Rachael E. J., Högler, Wolfgang, Karen Temple, I., Davies, Justin H., Gagunashvili, Andrey, Robinson, Iain C.A.F., Camper, Sally A., Davis, Shannon W., Cutillas, Pedro R., Gevers, Evelien F., Aoki, Yoko, Dattani, Mehul T., and Gaston-Massuet, Carles
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- 2021
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6. Visceral Adipose Tissue Immune Homeostasis Is Regulated by the Crosstalk between Adipocytes and Dendritic Cell Subsets
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Macdougall, Claire E., Wood, Elizabeth G., Loschko, Jakob, Scagliotti, Valeria, Cassidy, Féaron C., Robinson, Mark E., Feldhahn, Niklas, Castellano, Leandro, Voisin, Mathieu-Benoit, Marelli-Berg, Federica, Gaston-Massuet, Carles, Charalambous, Marika, and Longhi, M. Paula
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- 2018
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7. Tumor microenvironment defines the invasive phenotype of AIP-mutation-positive pituitary tumors
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Barry, Sayka, Carlsen, Eivind, Marques, Pedro, Stiles, Craig E., Gadaleta, Emanuela, Berney, Dan M., Roncaroli, Federico, Chelala, Claude, Solomou, Antonia, Herincs, Maria, Caimari, Francisca, Grossman, Ashley B., Crnogorac-Jurcevic, Tatjana, Haworth, Oliver, Gaston-Massuet, Carles, and Korbonits, Márta
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- 2019
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8. Role of Zic genes during neurulation
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Gaston-Massuet, Carles
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573.863871935335 - Abstract
Neurulation is the embryonic event that results in formation of the neural tube, the primordium of the central nervous system. Impairment of this process leads to neural tube defects (NTDs), which are among the commonest congenital malformations in humans. Zic1, 2, 3 and 4 encode a family of 2C2H-like zinc finger transcription factors of which two members, Zic2 and Zic3, have been implicated in the causation of NTDs. The aim of this thesis was to investigate the function of Zic genes during neural tube closure in the mouse embryo. The expression of Zic genes was examined at the time of neurulation by in situ hybridisation. All 4 Zic genes have partially overlapping but distinct expression domains, with Zic2 and Zic3 mRNA detected at the posterior neuropore region, consistent with the occurrence of spina bifida and sacral agenesis in Zic2 and Zic3 mutants. Expression of Zic2 was not altered during abnormal neurulation in the mouse mutants ct, Lp and Sp2H, indicating that Zic2 does not act downstream of these mutant genes in the production of NTDs. Zic3 expression was also unaffected in the ct and Sp2H mutants but showed downregulation in Lp homozygous embryos, suggesting that Zic3 may be regulated downstream of the Lp gene. A novel ENU-generated mouse model of spina bifida, the Kumba mouse (Zic2Ku), carries a mutation in the zinc finger domain region of Zic2. Morphological analysis of neurulation in Zic2Ku/Ku embryos showed that Zic2 is required for normal bending of the neural plate. Absence of dorsolateral bending during neural tube closure can explain the subsequent development of spina bifida in Zic2Ku/Ku embryos. In order to understand the molecular pathway by which Zic2 mediates its function, the yeast two-hybrid system was used to identify protein-binding partners. Capicua, p53 binding protein 1, Glis2 and Krox20 were among a series of genes whose protein products were found to interact with Zic2. These protein-protein interactions were confirmed by co-immunolocalisation studies of cultured transfected cells and by glutathione-S-transferase pull-down assays. In situ hybridisation studies demonstrated that Capicua is expressed in the posterior neuropore region of E9.5 embryos consistent with a role of these proteins in Zic2-dependent spina bifida. In conclusion, this thesis has established an early embryonic role for Zic2 in low spinal neurulation and has identified several binding proteins that may participate with Zic2 in the regulation of neural tube closure.
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- 2005
9. Transcription factor 7-like 1 is involved in hypothalamo–pituitary axis development in mice and humans
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Gaston-Massuet, Carles, McCabe, Mark J., Scagliotti, Valeria, Young, Rodrigo M., Carreno, Gabriela, Gregory, Louise C., Jayakody, Sujatha A., Pozzi, Sara, Gualtieri, Angelica, Basu, Basudha, Koniordou, Markela, Wu, Chun-I, Bancalari, Rodrigo E., Rahikkala, Elisa, Veijola, Riitta, Lopponen, Tuija, Graziola, Federica, Turton, James, Signore, Massimo, Gharavy, Seyedeh Neda Mousavy, Charolidi, Nicoletta, Sokol, Sergei Y., Andoniadou, Cynthia Lilian, Wilson, Stephen W., Merrill, Bradley J., Dattani, Mehul T., and Martinez-Barbera, Juan Pedro
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- 2016
10. Cell-Specific Gene Deletion Reveals the Antithrombotic Function of COX1 and Explains the Vascular COX1/Prostacyclin Paradox
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Mitchell, Jane A., Shala, Fisnik, Elghazouli, Youssef, Warner, Timothy D., Gaston-Massuet, Carles, Crescente, Marilena, Armstrong, Paul C., Herschman, Harvey R., and Kirkby, Nicholas S.
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- 2019
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11. Imprinted Dlk1 dosage as a size determinant of the mammalian pituitary gland.
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Scagliotti, Valeria, Vignola, Maria Lillina, Willis, Thea, Howard, Mark, Marinelli, Eugenia, Gaston-Massuet, Carles, Andoniadou, Cynthia, and Charalambous, Marika
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- 2023
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12. Novel FOXA2 mutation causes Hyperinsulinism, Hypopituitarism with Craniofacial and Endoderm-derived organ abnormalities
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Giri, Dinesh, Vignola, Maria Lillina, Gualtieri, Angelica, Scagliotti, Valeria, McNamara, Paul, Peak, Matthew, Didi, Mohammed, Gaston-Massuet, Carles, and Senniappan, Senthil
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- 2017
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13. Histopathology and molecular characterisation of intrauterine-diagnosed congenital craniopharyngioma
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Scagliotti, Valeria, Avagliano, Laura, Gualtieri, Angelica, Graziola, Federica, Doi, Patrizia, Chalker, Jane, Righini, Andrea, Korbonits, Marta, Bulfamante, Gaetano, Jacques, Thomas S., Massa, Valentina, and Gaston-Massuet, Carles
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- 2016
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14. Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans
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Gaston-Massuet, Carles, Andoniadou, Cynthia Lilian, Signore, Massimo, Jayakody, Sujatha A., Charolidi, Nicoletta, Kyeyune, Roger, Vernay, Bertrand, Jacques, Thomas S., Taketo, Makoto Mark, Le Tissier, Paul, Dattani, Mehul T., and Martinez-Barbera, Juan Pedro
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- 2011
15. FOXA2 as a Candidate Gene Responsible for Congenital Panhypopituitarism: A Review of the Literature
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Correia, Jorge, Corral, Laura Gómez, Kaygusuz, Sare Betül, Gualtieri, Angelica, and Gaston-Massuet, Carles
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ddc:616 - Published
- 2021
16. Identification of novel pathways involved in the pathogenesis of human adamantinomatous craniopharyngioma
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Andoniadou, Cynthia L., Gaston-Massuet, Carles, Reddy, Rukmini, Schneider, Ralph P., Blasco, Maria A., Le Tissier, Paul, Jacques, Thomas S., Pevny, Larysa H., Dattani, Mehul T., and Martinez-Barbera, Juan Pedro
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- 2012
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17. SOX2 regulates the hypothalamic-pituitary axis at multiple levels
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Jayakody, Sujatha A., Andoniadou, Cynthia L., Gaston-Massuet, Carles, Signore, Massimo, Cariboni, Anna, Bouloux, Pierre M., Tissier, Paul Le, Pevny, Larysa H., Dattani, Mehul T., and Martinez-Barbera, Juan P.
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Hypogonadism -- Genetic aspects -- Risk factors -- Research ,Transcription factors -- Physiological aspects -- Research ,Hypothalamic-pituitary-adrenal axis -- Physiological aspects -- Research ,Health care industry - Abstract
Sex-determining region Y (SRY) box 2 (SOX2) haploinsufficiency causes a form of hypopituitarism in humans that is characterized by gonadotrophin deficiency known as hypogonadotrophic hypogonadism. Here, we conditionally deleted Sox2 in mice to investigate the pathogenesis of hypogonadotrophic hypogonadism. First, we found that absence of SOX2 in the developing Rathke pouch of conditional embryos led to severe anterior lobe hypoplasia with drastically reduced expression of the pituitary-specific transcription factor POU class 1 homeobox 1 (POU1F1) as well as severe disruption of somatotroph and thyrotroph differentiation.In contrast, corticotrophs, rostral-tip POU1F1-independent thyrotrophs, and, interestingly, lactotrophs and gonadotrophs were less affected. Second, we identified a requirement for SOX2 in normal proliferation of periluminal progenitors; in its absence, insufficient precursors were available to produce all cell lineages of the anterior pituitary. Differentiated cells derived from precursors exiting cell cycle at early stages, including corticotrophs, rostral-tip thyrotrophs, and gonadotrophs, were generated, while hormone-producing cells originating from late-born precursors, such as somatotrophs and POU1F1-dependent thyrotrophs, were severely reduced. Finally, we found that 2 previously characterized patients with SOX2 haploinsufficiency and associated hypogonadotrophic hypogonadism had a measurable response to gonadotropin-releasing hormone (GnRH) stimulation, suggesting that it is not the absence of gonadotroph differentiation, but rather the deficient hypothalamic stimulation of gonadotrophs, that underlies typical hypogonadotrophic hypogonadism., Introduction Heterozygous mutations in sex-determining region Y (SRY) box 2 (SOX2) have been associated with major eye abnormalities (i.e., anophthalmia, microphthalmia, and coloboma), hypopituitarism characterized by pituitary hypoplasia on imaging, [...]
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- 2012
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18. Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin
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Crescente, Marilena, Armstrong, Paul C., Kirkby, Nicholas S., Edin, Matthew L., Chan, Melissa V., Lih, Fred B., Jiao, Jing, Maffucci, Tania, Allan, Harriet E., Mein, Charles A., Gaston-Massuet, Carles, Cottrell, Graeme S., Mitchell, Jane A., Zeldin, Darryl C., Herschman, Harvey R., and Warner, Timothy D.
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lipids (amino acids, peptides, and proteins) - Abstract
Aspirin prevents thrombosis by inhibiting platelet cyclooxygenase (COX)-1 activity and the production of thromboxane (Tx)A2 , a pro-thrombotic eicosanoid. However, the non-platelet actions of aspirin limit its antithrombotic effects. Here, we used platelet-COX-1-ko mice to define the platelet and non-platelet eicosanoids affected by aspirin. Mass-spectrometry analysis demonstrated blood from platelet-COX-1-ko and global-COX-1-ko mice produced similar eicosanoid profiles in vitro: for example, formation of TxA2 , prostaglandin (PG) F2α , 11-hydroxyeicosatraenoic acid (HETE), and 15-HETE was absent in both platelet- and global-COX-1-ko mice. Conversely, in vivo, platelet-COX-1-ko mice had a distinctly different profile from global-COX-1-ko or aspirin-treated control mice, notably significantly higher levels of PGI2 metabolite. Ingenuity Pathway Analysis (IPA) predicted that platelet-COX-1-ko mice would be protected from thrombosis, forming less pro-thrombotic TxA2 and PGE2 . Conversely, aspirin or lack of systemic COX-1 activity decreased the synthesis of anti-aggregatory PGI2 and PGD2 at non-platelet sites leading to predicted thrombosis increase. In vitro and in vivo thrombosis studies proved these predictions. Overall, we have established the eicosanoid profiles linked to inhibition of COX-1 in platelets and in the remainder of the cardiovascular system and linked them to anti- and pro-thrombotic effects of aspirin. These results explain why increasing aspirin dosage or aspirin addition to other drugs may lessen antithrombotic protection.
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- 2020
19. Variations in PROKR2, But Not PROK2, Are Associated With Hypopituitarism and Septo-optic Dysplasia
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McCabe, Mark J., Gaston-Massuet, Carles, Gregory, Louise C., Alatzoglou, Kyriaki S., Tziaferi, Vaitsa, Sbai, Oualid, Rondard, Philippe, Masumoto, Koh-hei, Nagano, Mamoru, Shigeyoshi, Yasufumi, Pfeifer, Marija, Hulse, Tony, Buchanan, Charles R., Pitteloud, Nelly, Martinez-Barbera, Juan-Pedro, and Dattani, Mehul T.
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- 2013
20. The imprinted Zdbf2 gene finely tunes control of feeding and growth in neonates.
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Glaser, Juliane, Iranzo, Julian, Borensztein, Maud, Marinucci, Mattia, Gualtieri, Angelica, Jouhanneau, Colin, Teissandier, Aurélie, Gaston-Massuet, Carles, and Bourc'his, Deborah
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- 2022
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21. Novel FGF8 Mutations Associated with Recessive Holoprosencephaly, Craniofacial Defects, and Hypothalamo-Pituitary Dysfunction
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McCabe, Mark J., Gaston-Massuet, Carles, Tziaferi, Vaitsa, Gregory, Louise C., Alatzoglou, Kyriaki S., Signore, Massimo, Puelles, Eduardo, Gerrelli, Dianne, Farooqi, I. Sadaf, Raza, Jamal, Walker, Joanna, Kavanaugh, Scott I., Tsai, Pei-San, Pitteloud, Nelly, Martinez-Barbera, Juan-Pedro, and Dattani, Mehul T.
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- 2011
22. Absence of SIX3 Mutations in Patients With Congenital Hypopituitarism
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Gaston-Massuet, Carles, Kelberman, Daniel, Dattani, Mehul, and Martinez-Barbera, Juan Pedro
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- 2009
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23. Dysgenesis and Dysfunction of the Pancreas and Pituitary Due to FOXA2 Gene Defects.
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Kaygusuz, Sare Betul, Ates, Esra Arslan, Vignola, Maria Lillina, Volkan, Burcu, Geckinli, Bilgen Bilge, Turan, Serap, Bereket, Abdullah, Gaston-Massuet, Carles, and Guran, Tulay
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DYSGENESIS ,PANCREAS ,PITUITARY gland - Abstract
Context: Developmental disorders of the pituitary gland leading to congenital hypopituitarism can either be isolated or associated with extrapituitary abnormalities (syndromic hypopituitarism). A large number of syndromic hypopituitarism cases are linked to mutations in transcription factors. The forkhead box A2 (FOXA2) is a transcription factor that plays a key role in the central nervous system, foregut, and pancreatic development. Objective: This work aims to characterize 2 patients with syndromic hypopituitarism due to FOXA2 gene defects. Results: We report a novel heterozygous nonsense c.616C > T(p.Q206X) variant that leads to a truncated protein that lacks part of the DNA-binding domain of FOXA2, resulting in impaired transcriptional activation of the glucose transporter type 2 (GLUT2)-luciferase reporter. The patient is the sixth patient described in the literature with a FOXA2 mutation, and the first patient exhibiting pancreatic hypoplasia. We also report a second patient with a novel de novo 8.53 Mb deletion of 20p11.2 that encompasses FOXA2, who developed diabetes mellitus that responded to sulfonylurea treatment. Conclusion: Our 2 cases broaden the molecular and clinical spectrum of FOXA2-related disease, reporting the first nonsense mutation and the first case of pancreatic dysgenesis. [ABSTRACT FROM AUTHOR]
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- 2021
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24. Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse
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Murdoch, Jennifer N., Henderson, Deborah J., Doudney, Kit, Gaston-Massuet, Carles, Phillips, Helen M., Paternotte, Caroline, Arkell, Ruth, Stanier, Philip, and Copp, Andrew J.
- Published
- 2003
25. WNT3A‐loaded exosomes enable cartilage repair.
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Thomas, Bethan L., Eldridge, Suzanne E., Nosrati, Babak, Alvarez, Mario, Thorup, Anne‐Sophie, Nalesso, Giovanna, Caxaria, Sara, Barawi, Aida, Nicholson, James G., Perretti, Mauro, Gaston‐Massuet, Carles, Pitzalis, Costantino, Maloney, Alison, Moore, Adrian, Jupp, Ray, and Dell'Accio, Francesco
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CARTILAGE regeneration ,EXTRACELLULAR vesicles ,WNT signal transduction ,EXTRACELLULAR matrix ,CARTILAGE cells ,WESTERN immunoblotting ,EXOSOMES ,CARTILAGE - Abstract
Cartilage defects repair poorly. Recent genetic studies suggest that WNT3a may contribute to cartilage regeneration, however the dense, avascular cartilage extracellular matrix limits its penetration and signalling to chondrocytes. Extracellular vesicles actively penetrate intact cartilage. This study investigates the effect of delivering WNT3a into large cartilage defects in vivo using exosomes as a delivery vehicle. Exosomes were purified by ultracentrifugation from conditioned medium of either L‐cells overexpressing WNT3a or control un‐transduced L‐cells, and characterized by electron microscopy, nanoparticle tracking analysis and marker profiling. WNT3a loaded on exosomes was quantified by western blotting and functionally characterized in vitro using the SUPER8TOPFlash reporter assay and other established readouts including proliferation and proteoglycan content. In vivo pathway activation was assessed using TCF/Lef:H2B‐GFP reporter mice. Wnt3a loaded exosomes were injected into the knees of mice, in which large osteochondral defects were surgically generated. The degree of repair was histologically scored after 8 weeks. WNT3a was successfully loaded on exosomes and resulted in activation of WNT signalling in vitro. In vivo, recombinant WNT3a failed to activate WNT signalling in cartilage, whereas a single administration of WNT3a loaded exosomes activated canonical WNT signalling for at least one week, and eight weeks later, improved the repair of osteochondral defects. WNT3a assembled on exosomes, is efficiently delivered into cartilage and contributes to the healing of osteochondral defects. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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26. A Novel SEMA3G Mutation in Two Siblings Affected by Syndromic GnRH Deficiency.
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Oleari, Roberto, André, Valentina, Lettieri, Antonella, Tahir, Sophia, Roth, Lise, Paganoni, Alyssa, Eberini, Ivano, Parravicini, Chiara, Scagliotti, Valeria, Cotellessa, Ludovica, Bedogni, Francesco, De Martini, Lisa Benedetta, Corridori, Maria Vittoria, Gulli, Simona, Augustin, Hellmut G., Gaston-Massuet, Carles, Hussain, Khalid, and Cariboni, Anna
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NEURON development ,PRECOCIOUS puberty ,KALLMANN syndrome ,GENETIC disorders ,SIBLINGS ,SYMPTOMS ,CELL culture - Abstract
Introduction: Gonadotropin-releasing hormone (GnRH) deficiency causes hypogonadotropic hypogonadism (HH), a rare genetic disorder that impairs sexual reproduction. HH can be due to defective GnRH-secreting neuron development or function and may be associated with other clinical signs in overlapping genetic syndromes. With most of the cases being idiopathic, genetics underlying HH is still largely unknown. Objective: To assess the contribution of mutated Semaphorin 3G (SEMA3G) in the onset of a syndromic form of HH, characterized by intellectual disability and facial dysmorphic features. Method: By combining homozygosity mapping with exome sequencing, we identified a novel variant in the SEMA3G gene. We then applied mouse as a model organism to examine SEMA3Gexpression and its functional requirement in vivo. Further, we applied homology modelling in silico and cell culture assays in vitro to validate the pathogenicity of the identified gene variant. Results: We found that (i) SEMA3G is expressed along the migratory route of GnRH neurons and in the developing pituitary, (ii) SEMA3G affects GnRH neuron development, but is redundant in the adult hypothalamic-pituitary-gonadal axis, and (iii) mutated SEMA3G alters binding properties in silico and in vitro to its PlexinA receptors and attenuates its effect on the migration of immortalized GnRH neurons. Conclusion: In silico, in vitro, and in vivo models revealed that SEMA3G regulates GnRH neuron migration and that its mutation affecting receptor selectivity may be responsible for the HH-related defects. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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27. Rings and bricks: Expression of cohesin components is dynamic during development and adult life
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Bettini, Laura Rachele, Graziola, Federica, Fazio, Grazia, Grazioli, Paolo, Scagliotti, Valeria, Pasquini, Mariavittoria, Cazzaniga, Giovanni, Biondi, Andrea, Larizza, Lidia, Selicorni, Angelo, Gaston-Massuet, Carles, Massa, Valentina, Bettini, L, Graziola, F, Fazio, G, Grazioli, P, Scagliotti, V, Pasquini, M, Cazzaniga, G, Biondi, A, Larizza, L, Selicorni, A, Gaston-Massuet, C, and Massa, V
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Chromosomal Proteins, Non-Histone ,Cell Cycle Proteins ,Article ,Histone Deacetylases ,Catalysi ,lcsh:Chemistry ,Inorganic Chemistry ,Mice ,De Lange Syndrome ,Animals ,Humans ,Genetic Predisposition to Disease ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,Gene Expression Profiling ,Hematopoietic tissue ,Organic Chemistry ,Gene Expression Regulation, Developmental ,Nuclear Proteins ,Proteins ,Computer Science Applications1707 Computer Vision and Pattern Recognition ,Phosphoproteins ,Hematopoiesis ,DNA-Binding Proteins ,Repressor Proteins ,Chondroitin Sulfate Proteoglycans ,lcsh:Biology (General) ,lcsh:QD1-999 ,Central nervous system ,Mutation ,Gene expression ,biological phenomena, cell phenomena, and immunity ,hematopoietic tissues ,Cohesin complex - Abstract
Cohesin complex components exert fundamental roles in animal cells, both canonical in cell cycle and non-canonical in gene expression regulation. Germline mutations in genes coding for cohesins result in developmental disorders named cohesinopaties, of which Cornelia de Lange syndrome (CdLS) is the best-known entity. However, a basic description of mammalian expression pattern of cohesins in a physiologic condition is still needed. Hence, we report a detailed analysis of expression in murine and human tissues of cohesin genes defective in CdLS. Using both quantitative and qualitative methods in fetal and adult tissues, cohesin genes were found to be ubiquitously and differentially expressed in human tissues. In particular, abundant expression was observed in hematopoietic and central nervous system organs. Findings of the present study indicate tissues which should be particularly sensitive to mutations, germline and/or somatic, in cohesin genes. Hence, this expression analysis in physiological conditions may represent a first core reference for cohesinopathies.
- Published
- 2018
28. Novel application of luciferase assay for the in vitro functional assessment of KAL1 variants in three females with septo-optic dysplasia (SOD)
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McCabe, Mark J., Hu, Youli, Gregory, Louise C., Gaston-Massuet, Carles, Alatzoglou, Kyriaki S., Saldanha, José W., Gualtieri, Angelica, Thankamony, Ajay, Hughes, Ieuan, Townshend, Sharron, Martinez-Barbera, Juan-Pedro, Bouloux, Pierre-Marc, and Dattani, Mehul T.
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Models, Molecular ,Extracellular Matrix Proteins ,Luciferase assay ,Kallmann syndrome ,Nerve Tissue Proteins ,In Vitro Techniques ,Biochemistry ,Polymorphism, Single Nucleotide ,Article ,Pedigree ,KAL1 ,Endocrinology ,Females ,Septo-Optic Dysplasia ,Pituitary Gland ,COS Cells ,Chlorocebus aethiops ,Animals ,Humans ,Female ,Luciferases ,Molecular Biology - Abstract
KAL1 is implicated in 5% of Kallmann syndrome cases, a disorder which genotypically overlaps with septo-optic dysplasia (SOD). To date, a reporter-based assay to assess the functional consequences of KAL1 mutations is lacking. We aimed to develop a luciferase assay for novel application to functional assessment of rare KAL1 mutations detected in a screen of 422 patients with SOD. Quantitative analysis was performed using L6-myoblasts stably expressing FGFR1, transfected with a luciferase-reporter vector containing elements of the FGF-responsive osteocalcin promoter. The two variants assayed [p.K185N, p.P291T], were detected in three females with SOD (presenting with optic nerve hypoplasia, midline and pituitary defects). Our novel assay revealed significant decreases in transcriptional activity [p.K185N: 21% (p, Highlights • We identified variations in X-linked KAL1 in three girls with septo-optic dysplasia. • We developed a luciferase assay for novel functional assessment of these variants. • Variants were loss of function but variably penetrant; other genes may be involved. • Cellular secretion of one of the mutant KAL1 proteins was partially disrupted. • We identified KAL1 expression in developing human pituitary by in situ hybridisation.
- Published
- 2015
29. Stem Cells, Self-Renewal, and Lineage Commitment in the Endocrine System.
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Mariniello, Katia, Ruiz-Babot, Gerard, McGaugh, Emily C., Nicholson, James G., Gualtieri, Angelica, Gaston-Massuet, Carles, Nostro, Maria Cristina, and Guasti, Leonardo
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STEM cells ,ENDOCRINE system ,PROGENITOR cells ,BIOLOGISTS ,COORDINATES - Abstract
The endocrine system coordinates a wide array of body functions mainly through secretion of hormones and their actions on target tissues. Over the last decades, a collective effort between developmental biologists, geneticists, and stem cell biologists has generated a wealth of knowledge related to the contribution of stem/progenitor cells to both organogenesis and self-renewal of endocrine organs. This review provides an up-to-date and comprehensive overview of the role of tissue stem cells in the development and self-renewal of endocrine organs. Pathways governing crucial steps in both development and stemness maintenance, and that are known to be frequently altered in a wide array of endocrine disorders, including cancer, are also described. Crucially, this plethora of information is being channeled into the development of potential new cell-based treatment modalities for endocrine-related illnesses, some of which have made it through clinical trials. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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30. Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
- Author
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Ewans, Lisa Jean, Colley, Alison, Gaston-Massuet, Carles, Gualtieri, Angelica, Cowley, Mark J., McCabe, Mark James, Anand, Deepti, Lachke, Salil A., Scietti, Luigi, Forneris, Federico, Ying Zhu, Ying, Kevin, Walsh, Corrina, Kirk, Edwin P., Miller, David, Giunta, Cecilia, Sillence, David, Dinger, Marcel, Buckley, Michael, and Roscioli, Tony
- Abstract
Background Pathogenic PLOD3 variants cause a connective tissue disorder (CTD) that has been described rarely. We further characterise this CTD and propose a clinical diagnostic label to improve recognition and diagnosis of PLOD3-related disease. Methods Reported PLOD3 phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant. PLOD3 mRNA expression in the developing embryo was analysed for tissue-specific localisation. Mouse microarray expression data were assessed for phylogenetic gene expression similarities across CTDs with overlapping clinical features. Results Key clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection. Collated clinical features showed most overlap with Stickler syndrome with variable features of Ehlers-Danlos syndrome (EDS) and epidermolysis bullosa (EB). Human lysyl hydroxylase 3/PLOD3 expression was localised to the developing cochlea, eyes, skin, forelimbs, heart and cartilage, mirroring the clinical phenotype of this disorder. Conclusion These data are consistent with pathogenic variants in PLOD3 resulting in a clinically distinct Sticklerlike syndrome with vascular complications and variable features of EDS and EB. Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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31. Constitutive Activation of β-Catenin in Conventional Dendritic Cells Increases the Insulin Reserve to Ameliorate the Development of Type 2 Diabetes in Mice.
- Author
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Macdougall, Claire E., Wood, Elizabeth G., Solomou, Antonia, Scagliotti, Valeria, Taketo, Makoto Mark, Gaston-Massuet, Carles, Marelli-Berg, Federica M., Charalambous, Marika, and Longhi, M. Paula
- Subjects
TYPE 2 diabetes ,DENDRITIC cells ,INSULIN ,IMMUNOREGULATION ,INSULIN resistance ,ADIPOSE tissues ,ANIMAL experimentation ,COMPARATIVE studies ,CYTOSKELETAL proteins ,FLOW cytometry ,IN situ hybridization ,ISLANDS of Langerhans ,RESEARCH methodology ,MEDICAL cooperation ,MICE ,POLYMERASE chain reaction ,RESEARCH ,WESTERN immunoblotting ,FLUORESCENCE in situ hybridization ,EVALUATION research - Abstract
β-Cell failure is central to the development of type 2 diabetes mellitus (T2DM). Dysregulation of metabolic and inflammatory processes during obesity contributes to the loss of islet function and impaired β-cell insulin secretion. Modulating the immune system, therefore, has the potential to ameliorate diseases. We report that inducing sustained expression of β-catenin in conventional dendritic cells (cDCs) provides a novel mechanism to enhance β-cell insulin secretion. Intriguingly, cDCs with constitutively activated β-catenin induced islet expansion by increasing β-cell proliferation in a model of diet-induced obesity. We further found that inflammation in these islets was reduced. Combined, these effects improved β-cell insulin secretion, suggesting a unique compensatory mechanism driven by cDCs to generate a greater insulin reserve in response to obesity-induced insulin resistance. Our findings highlight the potential of immune modulation to improve β-cell mass and function in T2DM. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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- View/download PDF
32. New insights into the molecular and cellular pathogenesis of human craniopharyngioma: do pituitary stem cells underlie the origin of these tumours?
- Author
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Andoniadou, Cynthia, Gaston-Massuet, Carles, Rukmini Reddy, Tissier, Paul Le, and Martinez-Barbera, Juan Pedro
- Published
- 2012
- Full Text
- View/download PDF
33. CyclinD1 Down-Regulation and Increased Apoptosis Are Common Features of Cohesinopathies.
- Author
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Fazio, Grazia, Gaston‐Massuet, Carles, Bettini, Laura Rachele, Graziola, Federica, Scagliotti, Valeria, Cereda, Anna, Ferrari, Luca, Mazzola, Mara, Cazzaniga, Gianni, Giordano, Antonio, Cotelli, Franco, Bellipanni, Gianfranco, Biondi, Andrea, Selicorni, Angelo, Pistocchi, Anna, and Massa, Valentina
- Subjects
- *
CYCLINS , *DOWNREGULATION , *APOPTOSIS , *COHESINS , *HUMAN genetic variation - Abstract
Genetic variants within components of the cohesin complex ( NIPBL, SMC1A, SMC3, RAD21, PDS5, ESCO2, HDAC8) are believed to be responsible for a spectrum of human syndromes known as 'cohesinopathies' that includes Cornelia de Lange Syndrome (CdLS). CdLS is a multiple malformation syndrome affecting almost any organ and causing severe developmental delay. Cohesinopathies seem to be caused by dysregulation of specific developmental pathways downstream of mutations in cohesin components. However, it is still unclear how mutations in different components of the cohesin complex affect the output of gene regulation. In this study, zebrafish embryos and SMC1A-mutated patient-derived fibroblasts were used to analyze abnormalities induced by SMC1A loss of function. We show that the knockdown of smc1a in zebrafish impairs neural development, increases apoptosis, and specifically down-regulates Ccnd1 levels. The same down-regulation of cohesin targets is observed in SMC1A-mutated patient fibroblasts. Previously, we have demonstrated that haploinsufficiency of NIPBL produces similar effects in zebrafish and in patients fibroblasts indicating a possible common feature for neurological defects and mental retardation in cohesinopathies. Interestingly, expression analysis of Smc1a and Nipbl in developing mouse embryos reveals a specific pattern in the hindbrain, suggesting a role for cohesins in neural development in vertebrates. J. Cell. Physiol. 231: 613-622, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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34. Cell death and cell proliferation in human spina bifida.
- Author
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Avagliano, Laura, Doi, Patrizia, Tosi, Delfina, Scagliotti, Valeria, Gualtieri, Angelica, Gaston‐Massuet, Carles, Pistocchi, Anna, Gallina, Andrea, Marconi, Anna Maria, Bulfamante, Gaetano, and Massa, Valentina
- Abstract
Background Spina bifida is a multifactorial congenital malformation of the central nervous system. The aim of this study was to ascertain the relevance of cell death/proliferation balance in human spina bifida and to assess autophagy distribution and levels during embryo-fetal development in neural tissue. Methods Five human cases with myelomeningocoele were compared with 10 healthy human controls and LC3 protein expression was also analyzed in mouse embryos. Cell death was evaluated using TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick end-labeling) assay; cell proliferation was studied by counting Ki67-positive cells, and autophagy was assessed by observing the presence of LC3 punctuate dots. Results Comparing human cases and controls (13 to 21 weeks of gestation), we observed a significant increase in TUNEL-positive cells in human spina bifida associated with a significantly decreased proliferation rate, indicating an alteration of the physiological cell rate homeostasis. LC3 distribution was found to be spatiotemporally regulated in both human and murine embryo-fetuses: in early pregnancy a diffuse and ubiquitous LC3 signal was detected. After neural tube closure, an intense LC3-positive signal, normally associated to extra energy requirement, was confined to the Lissauer's tract, the dorsolateral spinal zone containing centrally projecting axons from dorsal root ganglia, at any medullar levels. LC3 signal disappeared from 12 weeks of gestation. Conclusion In conclusion, this study confirms the fundamental role of cell death/proliferation balance during central nervous system development and reports the changing expression of LC3 protein in mouse and human neural tube. Birth Defects Research (Part A) 106:104-113, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
35. HESX1- and TCF3-mediated repression of Wnt/β-catenin targets is required for normal development of the anterior forebrain.
- Author
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Andoniadou, Cynthia L., Signore, Massimo, Young, Rodrigo M., Gaston-Massuet, Carles, Wilson, Stephen W., Fuchs, Elaine, and Martinez-Barbera, Juan Pedro
- Subjects
WNT genes ,GENE targeting ,TRANSCRIPTION factors ,PROSENCEPHALON ,GENE expression - Abstract
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-offunction 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. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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36. Genetic interaction between the homeobox transcription factors HESX1 and SIX3 is required for normal pituitary development
- Author
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Gaston-Massuet, Carles, Andoniadou, Cynthia L., Signore, Massimo, Sajedi, Ezat, Bird, Sophie, Turner, James M.A., and Martinez-Barbera, Juan Pedro
- Subjects
- *
DEVELOPMENTAL genetics , *PITUITARY gland physiology , *HOMEOBOX genes , *TRANSCRIPTION factors , *GENE expression , *LABORATORY mice , *EMBRYOS - Abstract
Abstract: Hesx1 has been shown to be essential for normal pituitary development. The homeobox gene Six3 is expressed in the developing pituitary gland during mouse development but its function in this tissue has been precluded by the fact that in the Six3-deficient embryos the pituitary gland is not induced. To gain insights into the function of Six3 during pituitary development we have generated Six3+/−;Hesx1Cre/+ double heterozygous mice. Strikingly, these mice show marked dwarfism, which is first detectable around weaning, and die by the 5th–6th week of age. Thyroid and gonad development is also impaired in these animals. Analysis of Six3+/−;Hesx1Cre/+ compound embryos indicates that hypopituitarism is the likely cause of these defects since pituitary development is severely impaired in these mutants. Similar to the Hesx1-deficient embryos, Rathke''s pouch is initially expanded in Six3+/−;Hesx1Cre/+ compound embryos due to an increase in cell proliferation. Subsequently, the anterior pituitary gland appears bifurcated, dysmorphic and occasionally ectopically misplaced in the nasopharyngeal cavity, but cell differentiation is unaffected. Our research has revealed a role for Six3 in normal pituitary development, which has likely been conserved during evolution as SIX3 is also expressed in the pituitary gland of the human embryo. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
37. DNMT1 interacts with the developmental transcriptional repressor HESX1
- Author
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Sajedi, Ezat, Gaston-Massuet, Carles, Andoniadou, Cynthia L., Signore, Massimo, Hurd, Paul J., Dattani, Mehul, and Martinez-Barbera, Juan Pedro
- Subjects
- *
GENES , *HEREDITY , *MOLECULAR genetics , *DNA - Abstract
Abstract: Hesx1 is a highly conserved homeobox gene present in vertebrates, but absent from invertebrates. Gene targeting experiments in mice have shown that this transcriptional repressor is required for normal forebrain and pituitary development. In humans, mutations in HESX1 impairing either its repressing activity or DNA binding properties lead to a comparable phenotype to that observed in Hesx1 deficient mice. In an attempt to gain insights into the molecular function of HESX1, we have performed a yeast two-hybrid screen and identified DNA methyltransferase 1 (DNMT1) as a HESX1 binding protein. We show that Dnmt1 is co-expressed with Hesx1 within the anterior forebrain and in the developing Rathke''s pouch. Mapping of the interacting regions indicates that the entire HESX1 protein is required to establish binding to a portion of the N-terminus of DNMT1 and its catalytic domain in the C-terminus. The HESX1–DNMT1 complexes can be immunoprecipitated in cells and co-localise in the nucleus. These results establish a link between HESX1 and DNMT1 and suggest a novel mechanism for the repressing properties of HESX1. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
38. Pituitary and Neuroendocrinology.
- Author
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Gevers, Evelien F., Gaston-Massuet, Carles, and de Roux, Nicolas
- Published
- 2014
39. Pituitary.
- Author
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Gevers, Evelien F., Gaston-Massuet, Carles, and Dattani, Mehul T.
- Published
- 2012
- Full Text
- View/download PDF
40. Identification of novel pathways involved in the pathogenesis of human adamantinomatous craniopharyngioma
- Author
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Martinez-Barbera, Juan Pedro, Reddy, Rukmini, Andoniadou, Cynthia L., Schneider, Ralph P., Blasco, Maria A., Gaston-Massuet, Carles, Dattani, Mehul T., Le Tissier, Paul, Jacques, Thomas S., and Pevny, Larysa H.
- Subjects
3. Good health - Abstract
Activating mutations in the gene encoding β-catenin have been identified in the paediatric form of human craniopharyngioma (adamantinomatous craniopharyngioma, ACP), a histologically benign but aggressive pituitary tumour accounting for up to 10% of paediatric intracranial tumours. Recently, we generated an ACP mouse model and revealed that, as in human ACP, nucleocytoplasmic accumulation of β-catenin (β-catnc) and over-activation of the Wnt/β-catenin pathway occurs only in a very small proportion of cells, which form clusters. Here, combining mouse genetics, fluorescence labelling and flow-sorting techniques, we have isolated these cells from tumorigenic mouse pituitaries and shown that the β-catnc cells are enriched for colony-forming cells when cultured in stem cell-promoting media, and have longer telomeres, indicating shared properties with normal pituitary progenitors/stem cells (PSCs). Global gene profiling analysis has revealed that these β-catnc cells express high levels of secreted mitogenic signals, such as members of the SHH, BMP and FGF family, in addition to several chemokines and their receptors, suggesting an important autocrine/paracrine role of these cells in the pathogenesis of ACP and a reciprocal communication with their environment. Finally, we highlight the clinical relevance of these findings by showing that these pathways are also up-regulated in the β-catnc cell clusters identified in human ACP. As well as providing further support to the concept that pituitary stem cells may play an important role in the oncogenesis of human ACP, our data reveal novel disease biomarkers and potential pharmacological targets for the treatment of these devastating childhood tumours.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-0957-9) contains supplementary material, which is available to authorized users.
41. 13-P115 Hesx1 antagonises canonical Wnt signalling in anterior forebrain and pituitary gland
- Author
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Andoniadou, Cynthia L., Gaston-Massuet, Carles, and Martinez-Barbera, Juan Pedro
- Published
- 2009
- Full Text
- View/download PDF
42. 06-P054 Molecular analysis of Hesx1 function in pituitary and hypothalamic development
- Author
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Jayakody, Sujatha A., Gaston-Massuet, Carles, Andoniadou, Cynthia L., Dattani, Mehul, and Matinez-Barbera, Juan Pedro
- Published
- 2009
- Full Text
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43. Neural plate morphogenesis during mouse neurulation is regulated by antagonism of Bmp signalling.
- Author
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Ybot-Gonzalez, Patricia, Gaston-Massuet, Carles, Girdler, Gemma, Klingensmith, John, Arkell, Ruth, Greene, Nicholas D. E., and Copp, Andrew J.
- Subjects
- *
NERVE tissue , *MORPHOGENESIS , *EMBRYOS , *BONE morphogenetic proteins , *LABORATORY mice - Abstract
Dorsolateral bending of the neural plate, an undifferentiated pseudostratified epithelium, is essential for neural tube closure in the mouse spinal region. If dorsolateral bending fails, spina bifida results. In the present study, we investigated the molecular signals that regulate the formation of dorsolateral hinge points (DLHPs). We show that Bmp2 expression correlates with upper spinal neurulation (in which DLHPs are absent); that Bmp2-null embryos exhibit premature, exaggerated DLHPs; and that the local release of Bmp2 inhibits neural fold bending. Therefore, Bmp signalling is necessary and sufficient to inhibit DLHPs. By contrast, the Bmp antagonist noggin is expressed dorsally in neural folds containing DLHPs, noggin-null embryos show markedly reduced dorsolateral bending and local release of noggin stimulates bending. Hence, Bmp antagonism is both necessary and sufficient to induce dorsolateral bending. The local release of Shh suppresses dorsal noggin expression, explaining the absence of DLHPs at high spinal levels, where notochordal expression of Shh is strong. DLHPs `break through' at low spinal levels, where Shh expression is weaker. Zic2 mutant embryos fail to express Bmp antagonists dorsally and lack DLHPs, developing severe spina bifida. Our findings reveal a molecular mechanism based on antagonism of Bmp signalling that underlies the regulation of DLHP formation during mouse spinal neural tube closure. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
44. Lack of the murine homeobox gene Hesx1 leads to a posterior transformation of the anterior forebrain.
- Author
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Andoniadou, Cynthia L., Signore, Massimo, Sajedi, Ezat, Gaston-Massuet, Carles, Kelberman, Daniel, Burns, Alan J., Itasaki, Nobue, Dattani, Mehul, and Martinez-Barbera, Juan Pedro
- Subjects
GENES ,PROSENCEPHALON ,BRAIN ,NERVE tissue ,TISSUES - Abstract
The homeobox gene Hesx1 is an essential repressor that is required within the anterior neural plate for normal forebrain development in mouse and humans. Combining genetic cell labelling and marker analyses, we demonstrate that the absence of Hesx1 leads to a posterior transformation of the anterior forebrain (AFB) during mouse development. Our data suggest that the mechanism underlying this transformation is the ectopic activation of Wnt/β-catenin signalling within the Hesx1 expression domain in the AFB. When ectopically expressed in the developing mouse embryo, Hesx1 alone cannot alter the normal fate of posterior neural tissue. However, conditional expression of Hesx1 within the AFB can rescue the forebrain defects observed in the Hesx1 mutants. The results presented here provide new insights into the function of Hesx1 in forebrain formation. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
45. ASPP2 Binds Par-3 and Controls the Polarity and Proliferation of Neural Progenitors during CNS Development
- Author
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Sottocornola, Roberta, Royer, Christophe, Vives, Virginie, Tordella, Luca, Zhong, Shan, Wang, Yihua, Ratnayaka, Indrika, Shipman, Mark, Cheung, Amanda, Gaston-Massuet, Carles, Ferretti, Patrizia, Molnár, Zoltán, and Lu, Xin
- Subjects
- *
PROTEIN binding , *CELL polarity , *CELL proliferation , *CENTRAL nervous system , *NEURONS , *CELL growth , *CELL migration - Abstract
Summary: Cell polarity plays a key role in the development of the central nervous system (CNS). Interestingly, disruption of cell polarity is seen in many cancers. ASPP2 is a haplo-insufficient tumor suppressor and an activator of the p53 family. In this study, we show that ASPP2 controls the polarity and proliferation of neural progenitors in vivo, leading to the formation of neuroblastic rosettes that resemble primitive neuroepithelial tumors. Consistent with its role in cell polarity, ASPP2 influences interkinetic nuclear migration and lamination during CNS development. Mechanistically, ASPP2 maintains the integrity of tight/adherens junctions. ASPP2 binds Par-3 and controls its apical/junctional localization without affecting its expression or Par-3/aPKCλ binding. The junctional localization of ASPP2 and Par-3 is interdependent, suggesting that they are prime targets for each other. These results identify ASPP2 as a regulator of Par-3, which plays a key role in controlling cell proliferation, polarity, and tissue organization during CNS development. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
46. Ephrin-B2 is critical regulator of endocrine organ development.
- Author
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Jimenez, Fernando Abollo, Gualtieri, Angelica, Scagliotti, Valeria, and Gaston-Massuet, Carles
- Subjects
- *
EPHRINS , *PITUITARY development , *CELL differentiation , *HYPOPITUITARISM , *IMMUNOSTAINING - Published
- 2017
- Full Text
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47. Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma.
- Author
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Mariniello K, Pittaway JFH, Altieri B, Borges KS, Hadjidemetriou I, Ribeiro C, Ruiz-Babot G, Lim JA, Foster J, Cleaver J, Sosabowski J, Rahman N, Doroszko M, Hantel C, Sigala S, Abate A, Tamburello M, Kiseljak-Vassiliades K, Wierman M, Parvanta L, Abdel-Aziz TE, Chung TT, Di Marco A, Palazzo F, Gomez-Sanchez CE, Taylor DR, Rayner O, Ronchi CL, Gaston-Massuet C, Sbiera S, Drake WM, Rognoni E, Kroiss M, Breault DT, Fassnacht M, and Guasti L
- Abstract
Disruption of processes involved in tissue development and homeostatic self-renewal is increasingly implicated in cancer initiation, progression, and recurrence. The adrenal cortex is a dynamic tissue that undergoes life-long turnover. Here, using genetic fate mapping and murine adrenocortical carcinoma (ACC) models, we have identified a population of adrenocortical stem cells that express delta-like non-canonical Notch ligand 1 (DLK1). These cells are active during development, near dormant postnatally but are re-expressed in ACC. In a study of over 200 human ACC samples, we have shown DLK1 expression is ubiquitous and is an independent prognostic marker of recurrence-free survival. Paradoxically, despite its progenitor role, spatial transcriptomic analysis has identified DLK1 expressing cell populations to have increased steroidogenic potential in human ACC, a finding also observed in four human and one murine ACC cell lines. Finally, the cleavable DLK1 ectodomain is measurable in patients' serum and can discriminate between ACC and other adrenal pathologies with high sensitivity and specificity to aid in diagnosis and follow-up of ACC patients. These data demonstrate a prognostic role for DLK1 in ACC, detail its hierarchical expression in homeostasis and oncogenic transformation and propose a role for its use as a biomarker in this malignancy., Competing Interests: Declaration of interests All authors declare no conflicts of interest.
- Published
- 2024
- Full Text
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48. Dual mechanism underlying failure of neural tube closure in the Zic2 mutant mouse.
- Author
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Escuin S, Rose Raza-Knight S, Savery D, Gaston-Massuet C, Galea GL, Greene NDE, and Copp AJ
- Subjects
- Mice, Animals, Humans, Neural Tube metabolism, Actomyosin metabolism, Neurulation, Mammals metabolism, Nuclear Proteins metabolism, Transcription Factors metabolism, Spinal Dysraphism, Neural Tube Defects genetics
- Abstract
Understanding the molecular mechanisms that lead to birth defects is an important step towards improved primary prevention. Mouse embryos homozygous for the Kumba (Ku) mutant allele of Zic2 develop severe spina bifida with complete lack of dorsolateral hinge points (DLHPs) in the neuroepithelium. Bone morphogenetic protein (BMP) signalling is overactivated in Zic2Ku/Ku embryos, and the BMP inhibitor dorsomorphin partially rescues neural tube closure in cultured embryos. RhoA signalling is also overactivated, with accumulation of actomyosin in the Zic2Ku/Ku neuroepithelium, and the myosin inhibitor Blebbistatin partially normalises neural tube closure. However, dorsomorphin and Blebbistatin differ in their effects at tissue and cellular levels: DLHP formation is rescued by dorsomorphin but not Blebbistatin, whereas abnormal accumulation of actomyosin is rescued by Blebbistatin but not dorsomorphin. These findings suggest a dual mechanism of spina bifida origin in Zic2Ku/Ku embryos: faulty BMP-dependent formation of DLHPs and RhoA-dependent F-actin accumulation in the neuroepithelium. Hence, we identify a multi-pathway origin of spina bifida in a mammalian system that may provide a developmental basis for understanding the corresponding multifactorial human defects., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)
- Published
- 2023
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49. Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin.
- Author
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Crescente M, Armstrong PC, Kirkby NS, Edin ML, Chan MV, Lih FB, Jiao J, Maffucci T, Allan HE, Mein CA, Gaston-Massuet C, Cottrell GS, Mitchell JA, Zeldin DC, Herschman HR, and Warner TD
- Subjects
- Animals, Arachidonic Acid administration & dosage, Blood Platelets drug effects, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Thrombosis drug therapy, Thrombosis pathology, Aspirin pharmacology, Blood Platelets metabolism, Cyclooxygenase 1 physiology, Cyclooxygenase Inhibitors pharmacology, Eicosanoids metabolism, Membrane Proteins physiology, Thrombosis metabolism
- Abstract
Aspirin prevents thrombosis by inhibiting platelet cyclooxygenase (COX)-1 activity and the production of thromboxane (Tx)A
2 , a pro-thrombotic eicosanoid. However, the non-platelet actions of aspirin limit its antithrombotic effects. Here, we used platelet-COX-1-ko mice to define the platelet and non-platelet eicosanoids affected by aspirin. Mass-spectrometry analysis demonstrated blood from platelet-COX-1-ko and global-COX-1-ko mice produced similar eicosanoid profiles in vitro: for example, formation of TxA2 , prostaglandin (PG) F2α , 11-hydroxyeicosatraenoic acid (HETE), and 15-HETE was absent in both platelet- and global-COX-1-ko mice. Conversely, in vivo, platelet-COX-1-ko mice had a distinctly different profile from global-COX-1-ko or aspirin-treated control mice, notably significantly higher levels of PGI2 metabolite. Ingenuity Pathway Analysis (IPA) predicted that platelet-COX-1-ko mice would be protected from thrombosis, forming less pro-thrombotic TxA2 and PGE2 . Conversely, aspirin or lack of systemic COX-1 activity decreased the synthesis of anti-aggregatory PGI2 and PGD2 at non-platelet sites leading to predicted thrombosis increase. In vitro and in vivo thrombosis studies proved these predictions. Overall, we have established the eicosanoid profiles linked to inhibition of COX-1 in platelets and in the remainder of the cardiovascular system and linked them to anti- and pro-thrombotic effects of aspirin. These results explain why increasing aspirin dosage or aspirin addition to other drugs may lessen antithrombotic protection., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)- Published
- 2020
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50. Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation.
- Author
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Gregory LC, Ferreira CB, Young-Baird SK, Williams HJ, Harakalova M, van Haaften G, Rahman SA, Gaston-Massuet C, Kelberman D, GOSgene, Qasim W, Camper SA, Dever TE, Shah P, Robinson ICAF, and Dattani MT
- Subjects
- Amino Acid Substitution, Apoptosis, Brain diagnostic imaging, Brain metabolism, Cell Line, Child, Preschool, Eukaryotic Initiation Factor-2 chemistry, Eukaryotic Initiation Factor-2 metabolism, Gene Knockdown Techniques, Humans, Hypopituitarism diagnosis, In Situ Hybridization, Infant, Magnetic Resonance Imaging, Mutation, Pedigree, Polymorphism, Single Nucleotide, Protein Biosynthesis, Eukaryotic Initiation Factor-2 genetics, Genes, X-Linked, Glucose metabolism, Hypopituitarism etiology, Hypopituitarism metabolism, Phenotype
- Abstract
Background: The heterotrimeric GTP-binding protein eIF2 forms a ternary complex with initiator methionyl-tRNA and recruits it to the 40S ribosomal subunit for start codon selection and thereby initiates protein synthesis. Mutations in EIF2S3, encoding the eIF2γ subunit, are associated with severe intellectual disability and microcephaly, usually as part of MEHMO syndrome., Methods: Exome sequencing of the X chromosome was performed on three related males with normal head circumferences and mild learning difficulties, hypopituitarism (GH and TSH deficiencies), and an unusual form of glucose dysregulation. In situ hybridisation on human embryonic tissue, EIF2S3-knockdown studies in a human pancreatic cell line, and yeast assays on the mutated corresponding eIF2γ protein, were performed in this study., Findings: We report a novel hemizygous EIF2S3 variant, p.Pro432Ser, in the three boys (heterozygous in their mothers). EIF2S3 expression was detectable in the developing pituitary gland and pancreatic islets of Langerhans. Cells lacking EIF2S3 had increased caspase activity/cell death. Impaired protein synthesis and relaxed start codon selection stringency was observed in mutated yeast., Interpretation: Our data suggest that the p.Pro432Ser mutation impairs eIF2γ function leading to a relatively mild novel phenotype compared with previous EIF2S3 mutations. Our studies support a critical role for EIF2S3 in human hypothalamo-pituitary development and function, and glucose regulation, expanding the range of phenotypes associated with EIF2S3 mutations beyond classical MEHMO syndrome. Untreated hypoglycaemia in previous cases may have contributed to their more severe neurological impairment and seizures in association with impaired EIF2S3. FUND: GOSH, MRF, BRC, MRC/Wellcome Trust and NIGMS funded this study., (Copyright © 2019. Published by Elsevier B.V.)
- Published
- 2019
- Full Text
- View/download PDF
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