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2014 ; 28
(9
): 1471-86
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Wnt signaling inhibits adrenal steroidogenesis by cell-autonomous and
non-cell-autonomous mechanisms
#MMPMID25029241
Walczak EM
; Kuick R
; Finco I
; Bohin N
; Hrycaj SM
; Wellik DM
; Hammer GD
Mol Endocrinol
2014[Sep]; 28
(9
): 1471-86
PMID25029241
show ga
Wnt/?-catenin (?cat) signaling is critical for adrenal homeostasis. To elucidate
how Wnt/?cat signaling elicits homeostatic maintenance of the adrenal cortex, we
characterized the identity of the adrenocortical Wnt-responsive population. We
find that Wnt-responsive cells consist of sonic hedgehog (Shh)-producing
adrenocortical progenitors and differentiated, steroidogenic cells of the zona
glomerulosa, but not the zona fasciculata and rarely cells that are actively
proliferating. To determine potential direct inhibitory effects of ?cat signaling
on zona fasciculata-associated steroidogenesis, we used the mouse ATCL7
adrenocortical cell line that serves as a model system of
glucocorticoid-producing fasciculata cells. Stimulation of ?cat signaling caused
decreased corticosterone release consistent with the observed reduced
transcription of steroidogenic genes Cyp11a1, Cyp11b1, Star, and Mc2r. Decreased
steroidogenic gene expression was correlated with diminished steroidogenic factor
1 (Sf1; Nr5a1) expression and occupancy on steroidogenic promoters. Additionally,
?cat signaling suppressed the ability of Sf1 to transactivate steroidogenic
promoters independent of changes in Sf1 expression level. To investigate
Sf1-independent effects of ?cat on steroidogenesis, we used Affymetrix gene
expression profiling of Wnt-responsive cells in vivo and in vitro. One candidate
gene identified, Ccdc80, encodes a secreted protein with unknown signaling
mechanisms. We report that Ccdc80 is a novel ?cat-regulated gene in
adrenocortical cells. Treatment of adrenocortical cells with media containing
secreted Ccdc80 partially phenocopies ?cat-induced suppression of
steroidogenesis, albeit through an Sf1-independent mechanism. This study reveals
multiple mechanisms of ?cat-mediated suppression of steroidogenesis and suggests
that Wnt/?cat signaling may regulate adrenal homeostasis by inhibiting
fasciculata differentiation and promoting the undifferentiated state of
progenitor cells.
|*Wnt Signaling Pathway
[MESH]
|Adrenal Cortex Hormones/metabolism
[MESH]
|Adrenal Cortex/*metabolism
[MESH]
|Animals
[MESH]
|Cell Differentiation
[MESH]
|Chromatin Immunoprecipitation
[MESH]
|DNA-Binding Proteins/metabolism
[MESH]
|Extracellular Matrix Proteins
[MESH]
|Gene Expression Profiling
[MESH]
|Gene Expression Regulation
[MESH]
|Glucocorticoids/metabolism
[MESH]
|Glycoproteins/metabolism
[MESH]
|HEK293 Cells
[MESH]
|Hedgehog Proteins/metabolism
[MESH]
|Homeostasis
[MESH]
|Humans
[MESH]
|Intercellular Signaling Peptides and Proteins/metabolism
[MESH]
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