Cushing's Syndrome and Fetal Features Resurgence in Adrenal Cortex–Specific Prkar1a Knockout Mice
| Autor: | Sahut-Barnola, Isabelle, De Joussineau, Cyrille, VAL, Pierre, Lambert-Langlais, Sarah, Damon, Christelle, Lefrançois-Martinez, Anne-Marie, Martinez, Anne-Marie, Pointud, Jean-Christophe, Marceau, Geoffroy, Sapin, Vincent, Tissier, Frédérique, Ragazzon, Bruno, Bertherat, Jérôme, Kirschner, Lawrence, Stratakis, Constantine, Martinez, Antoine |
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| Přispěvatelé: | Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Laboratoire de Biochimie, Centre Hospitalier Universitaire de Clermont-Ferrand, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Section on Endocrinology and Genetics, National Institutes of Health (NIH)-National Institute of Child Health and Human Development, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Nutrition Humaine (UNH), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Laoratoire de Biochimie, Service de Biochimie et Génétique Moléculaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Department of Medical Biochemistry and Molecular Biology, CHU Clermont-Ferrand, CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP) |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Male
Cancer Research [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] Cushing syndrome Mice 0302 clinical medicine PRKAR1A Cushing Syndrome Genetics (clinical) ComputingMilieux_MISCELLANEOUS Mice Knockout 0303 health sciences education.field_of_study Adrenal cortex Steroid 17-alpha-Hydroxylase medicine.anatomical_structure Oncology/Adrenal Cortex Female medicine.drug Research Article Signal Transduction medicine.medical_specialty lcsh:QH426-470 Cyclic AMP-Dependent Protein Kinase RIalpha Subunit Population 030209 endocrinology & metabolism [SDV.CAN]Life Sciences [q-bio]/Cancer Adrenocorticotropic hormone Biology 03 medical and health sciences Diabetes and Endocrinology/Adrenal Cortex Adrenocorticotropic Hormone Internal medicine [SDV.BA.ZV]Life Sciences [q-bio]/Animal biology/Vertebrate Zoology Genetics medicine Animals Humans Diabetes and Endocrinology/Multiple Endocrine Disorders and Neoplasias education Molecular Biology Carney complex Ecology Evolution Behavior and Systematics 030304 developmental biology Hydrocortisone Cell Proliferation Oncology/Multiple Endocrine Disorders and Neoplasias medicine.disease Cyclic AMP-Dependent Protein Kinases lcsh:Genetics Endocrinology [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis Genetics and Genomics/Disease Models Developmental Biology/Cell Differentiation Adrenal Cortex Primary pigmented nodular adrenocortical disease |
| Zdroj: | PLoS Genetics PLoS Genetics, Public Library of Science, 2010, 6 (6), pp.e1000980. ⟨10.1371/journal.pgen.1000980⟩ PLoS Genetics, Public Library of Science, 2010, 6 (6), ⟨10.1371/journal.pgen.1000980⟩ PLoS Genetics, 2010, 6 (6), ⟨10.1371/journal.pgen.1000980⟩ PLoS Genetics, Vol 6, Iss 6, p e1000980 (2010) |
| ISSN: | 1553-7390 1553-7404 |
| DOI: | 10.1371/journal.pgen.1000980⟩ |
| Popis: | Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 α-regulatory subunit (R1α) of the cAMP–dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1α loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1α loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1α is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD. Author Summary Carney complex is a rare familial disease characterized by a predisposition to develop multiple endocrine tumors and highly morbid syndromes due to endocrine overactivities. Its most frequent endocrine manifestation, hypersecretion of glucocorticoids i.e. Cushing's syndrome, is caused by micronodular adrenal gland hyperplasia, an unusual neoplasia which combines both hyperplastic and atrophic areas. Inactivating mutations of the gene encoding the regulatory subunit 1α (R1α) of the cAMP–dependent protein kinase were frequently found in these patients, but the causal link between loss of R1α and onset of this adrenal disorder had not yet been established. Here, we describe the first mouse model mimicking this disease and provide mechanistic insights into endocrine overactivity and neoplastic transformation. Indeed, we show that lack of R1α induces autonomous expression of genes involved in steroid biosynthesis and resurgence of hyperplastic fetal-like cells with concomitant defects in cell renewal of the adult cortex. Our data therefore represent a substantial conceptual advance on the cellular dynamics involved in adrenal gland homeostasis. They suggest that regression of fetal structures may be important to establish normal endocrine functions and to allow cell renewal in the definitive cortex. Failure to clear out cells of fetal features in R1α-deficient adrenals leads to morbid hyperplasia. |
| Databáze: | OpenAIRE |
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