Sonic hedgehog signaling regulates the expression of insulin-like growth factor binding protein-6 during fetal prostate development

Dev Dyn. 2005 Jul;233(3):829-36. doi: 10.1002/dvdy.20414.

Abstract

At the onset of ductal morphogenesis in the developing prostate, Shh expression condenses at evaginations of urogenital sinus epithelium and activates Gli transcription factors in the adjacent mesenchyme. Abrogation of Hedgehog signaling disrupts proper prostatic budding, ductal growth, and branching. We now show that Hedgehog signaling regulates the expression of insulin-like growth factor binding protein-6 (Igfbp-6) in the developing mouse prostate. Igfbp-6 is a secreted factor that specifically binds insulin-like growth factor-II (IGF-II), prevents its binding to the IGF-I receptor, and is thought to regulate the activity of IGF-II in growth and differentiation. Igfbp-6 is expressed in both the developing and adult prostate. In the urogenital sinus, Igfbp-6 mRNA colocalized with Ptc1 and Gli1 mRNA in the mesenchyme, while Igfbp-6 protein was found in both the mesenchymal and epithelial layers. Exogenous Shh peptide induced expression of Igfbp-6 in the developing prostate while the chemical inhibitor of Hedgehog signaling, cyclopamine, reduced its expression. These studies show that Igfbp-6 is an actual target of Shh signaling in the urogenital sinus and provide the first evidence for a linkage between the Hedgehog and IGF signaling pathways in prostate development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Fetus / embryology
  • Fetus / metabolism*
  • Gene Expression Regulation, Developmental* / genetics
  • Hedgehog Proteins
  • Insulin-Like Growth Factor Binding Protein 6 / genetics
  • Insulin-Like Growth Factor Binding Protein 6 / metabolism*
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kruppel-Like Transcription Factors
  • Male
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Patched Receptors
  • Patched-1 Receptor
  • Prostate / embryology*
  • Prostate / growth & development
  • Prostate / metabolism*
  • Receptors, Cell Surface
  • Signal Transduction*
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Up-Regulation
  • Veratrum Alkaloids / pharmacology
  • Zinc Finger Protein GLI1

Substances

  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Insulin-Like Growth Factor Binding Protein 6
  • Intracellular Signaling Peptides and Proteins
  • Kruppel-Like Transcription Factors
  • Membrane Proteins
  • Patched Receptors
  • Patched-1 Receptor
  • Ptch1 protein, mouse
  • Receptors, Cell Surface
  • Trans-Activators
  • Transcription Factors
  • Veratrum Alkaloids
  • Zinc Finger Protein GLI1
  • cyclopamine