title: Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice.
abstract: 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 alpha-regulatory subunit (R1alpha) of the cAMP-dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1alpha 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, R1alpha 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 R1alpha 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.
authors.affiliation: CNRS UMR6247, Génétique Reproduction et Développement, Clermont Université, Aubière, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sahut-Barnola
authors.forename: Cyrille
authors.initials: C
authors.lastname: de Joussineau
authors.forename: Pierre
authors.initials: P
authors.lastname: Val
authors.forename: Sarah
authors.initials: S
authors.lastname: Lambert-Langlais
authors.forename: Christelle
authors.initials: C
authors.lastname: Damon
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lefrançois-Martinez
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Pointud
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Marceau
authors.forename: Vincent
authors.initials: V
authors.lastname: Sapin
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kirschner
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.forename: Antoine
authors.initials: A
authors.lastname: Martinez
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D003480:Cushing Syndrome / Q000196:embryology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000172:deficiency / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517835:Prkar1a protein, mouse; D000324:Adrenocorticotropic Hormone; D013254:Steroid 17-alpha-Hydroxylase; D017868:Cyclic AMP-Dependent Protein Kinases