Wnt signaling in estrogen-induced lactotroph proliferation.
Prolactinomas are the most common type of functioning pituitary adenoma in humans, but the control of lactotroph proliferation remains unclear. Here, using microarray analysis, we show that estrogen treatment increased expression of Wnt4 mRNA in adult Fischer rat pituitary tissue. Dual immunofluorescence analysis revealed that Wnt4 expression was not confined to lactotrophs, but that it was expressed in all anterior pituitary cell types. Estradiol induced proliferation in the somatolactotroph GH3 cell line, in parallel with Wnt4 mRNA and protein induction. A reporter gene assay for TCF- and LEF-dependent transcription revealed that there was no activation of the canonical Wnt pathway in GH3 cells upon stimulation with Wnt-conditioned culture medium or coexpression of constitutively active mutant β-catenin. Expression of β-catenin in both GH3 cells and normal rat anterior pituitary cells was restricted to the cell membrane and was unaltered by treatment with estradiol, with no nuclear β-catenin being detected under any of the conditions tested. We show for the first time that Wnt4 affects non-canonical signaling in the pituitary by inhibiting Ca(2+) oscillations in GH3 cells, although the downstream effects are as yet unknown. In summary, Wnt4 is expressed in the adult pituitary gland, and its expression is increased by estrogen exposure, suggesting that its involvement in adult tissue plasticity is likely to involve β-catenin-independent signaling pathways.
Endocrinology & Diabetes Group, Faculty of Medical & Human Sciences, AV Hill Building, Oxford Road, University of Manchester, Manchester M13 9PT, UK.
Adam
A
Giles
Frederic
F
Madec
Sönke
S
Friedrichsen
Karen
K
Featherstone
Tom
T
Chambers
Claire V
CV
Harper
Julia
J
Resch
Georg
G
Brabant
Julian R E
JR
Davis
D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D052682:Lactotrophs / Q000166:cytology* / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060528:Wnt4 Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D004967:Estrogens; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555583:Wnt4 protein, rat; D051176:beta Catenin; D002118:Calcium
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