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Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration.

Publication ,  Journal Article
Le, V; He, Y; Aldahl, J; Hooker, E; Yu, E-J; Olson, A; Kim, WK; Lee, D-H; Wong, M; Sheng, R; Mi, J; Geradts, J; Cunha, GR; Sun, Z
Published in: PLoS Genet
January 2020

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.

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

January 2020

Volume

16

Issue

1

Start / End Page

e1008588

Location

United States

Related Subject Headings

  • Zinc Finger Protein GLI1
  • Transforming Growth Factor beta
  • Signal Transduction
  • Regeneration
  • Receptors, Androgen
  • Prostate
  • Morphogenesis
  • Mice
  • Mesenchymal Stem Cells
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
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Le, V., He, Y., Aldahl, J., Hooker, E., Yu, E.-J., Olson, A., … Sun, Z. (2020). Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration. PLoS Genet, 16(1), e1008588. https://doi.org/10.1371/journal.pgen.1008588
Le, Vien, Yongfeng He, Joseph Aldahl, Erika Hooker, Eun-Jeong Yu, Adam Olson, Won Kyung Kim, et al. “Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration.PLoS Genet 16, no. 1 (January 2020): e1008588. https://doi.org/10.1371/journal.pgen.1008588.
Le V, He Y, Aldahl J, Hooker E, Yu E-J, Olson A, et al. Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration. PLoS Genet. 2020 Jan;16(1):e1008588.
Le, Vien, et al. “Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration.PLoS Genet, vol. 16, no. 1, Jan. 2020, p. e1008588. Pubmed, doi:10.1371/journal.pgen.1008588.
Le V, He Y, Aldahl J, Hooker E, Yu E-J, Olson A, Kim WK, Lee D-H, Wong M, Sheng R, Mi J, Geradts J, Cunha GR, Sun Z. Loss of androgen signaling in mesenchymal sonic hedgehog responsive cells diminishes prostate development, growth, and regeneration. PLoS Genet. 2020 Jan;16(1):e1008588.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

January 2020

Volume

16

Issue

1

Start / End Page

e1008588

Location

United States

Related Subject Headings

  • Zinc Finger Protein GLI1
  • Transforming Growth Factor beta
  • Signal Transduction
  • Regeneration
  • Receptors, Androgen
  • Prostate
  • Morphogenesis
  • Mice
  • Mesenchymal Stem Cells
  • Male