Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration.
Animals
Cells, Cultured
Epithelial Cells
/ cytology
Hedgehog Proteins
/ metabolism
Male
Mesenchymal Stem Cells
/ cytology
Mice
Morphogenesis
Prostate
/ cytology
Receptors, Androgen
/ metabolism
Regeneration
Signal Transduction
Transforming Growth Factor beta
/ metabolism
Zinc Finger Protein GLI1
/ genetics
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
09
09
2019
accepted:
29
12
2019
revised:
24
01
2020
pubmed:
14
1
2020
medline:
14
4
2020
entrez:
14
1
2020
Statut:
epublish
Résumé
Prostate embryonic development, pubertal and adult growth, maintenance, and regeneration are regulated through androgen signaling-mediated mesenchymal-epithelial interactions. Specifically, the essential role of mesenchymal androgen signaling in the development of prostate epithelium has been observed for over 30 years. However, the identity of the mesenchymal cells responsible for this paracrine regulation and related mechanisms are still unknown. Here, we provide the first demonstration of an indispensable role of the androgen receptor (AR) in sonic hedgehog (SHH) responsive Gli1-expressing cells, in regulating prostate development, growth, and regeneration. Selective deletion of AR expression in Gli1-expressing cells during embryogenesis disrupts prostatic budding and impairs prostate development and formation. Tissue recombination assays showed that urogenital mesenchyme (UGM) containing AR-deficient mesenchymal Gli1-expressing cells combined with wildtype urogenital epithelium (UGE) failed to develop normal prostate tissue in the presence of androgens, revealing the decisive role of AR in mesenchymal SHH responsive cells in prostate development. Prepubescent deletion of AR expression in Gli1-expressing cells resulted in severe impairment of androgen-induced prostate growth and regeneration. RNA-sequencing analysis showed significant alterations in signaling pathways related to prostate development, stem cells, and organ morphogenesis in AR-deficient Gli1-expressing cells. Among these altered pathways, the transforming growth factor β1 (TGFβ1) pathway was up-regulated in AR-deficient Gli1-expressing cells. We further demonstrated the activation of TGFβ1 signaling in AR-deleted prostatic Gli1-expressing cells, which inhibits prostate epithelium growth through paracrine regulation. These data demonstrate a novel role of the AR in the Gli1-expressing cellular niche for regulating prostatic cell fate, morphogenesis, and renewal, and elucidate the mechanism by which mesenchymal androgen-signaling through SHH-responsive cells elicits the growth and regeneration of prostate epithelium.
Identifiants
pubmed: 31929563
doi: 10.1371/journal.pgen.1008588
pii: PGENETICS-D-19-01504
pmc: PMC6980684
doi:
Substances chimiques
Gli1 protein, mouse
0
Hedgehog Proteins
0
Receptors, Androgen
0
Transforming Growth Factor beta
0
Zinc Finger Protein GLI1
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008588Subventions
Organisme : NCI NIH HHS
ID : R01 CA070297
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA166894
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA190021
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK104941
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interest exist.
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