Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice.
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.
Sahut-Barnola
Isabelle
I
CNRS UMR6247, Génétique Reproduction et Développement, Clermont Université, Aubière, France.
de Joussineau
Cyrille
C
Val
Pierre
P
Lambert-Langlais
Sarah
S
Damon
Christelle
C
Lefrançois-Martinez
Anne-Marie
AM
Pointud
Jean-Christophe
JC
Marceau
Geoffroy
G
Sapin
Vincent
V
Tissier
Frédérique
F
Ragazzon
Bruno
B
Bertherat
Jérôme
J
Kirschner
Lawrence S
LS
Stratakis
Constantine A
CA
Martinez
Antoine
A
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
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