Sonic hedgehog signaling regulates the expression of insulin-like growth factor binding protein-6 during fetal prostate development.
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.
Lipinski
Robert J
RJ
Division of Urology, Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin 53792, USA.
Cook
Crist H
CH
Barnett
Daniel H
DH
Gipp
Jerry J
JJ
Peterson
Richard E
RE
Bushman
Wade
W
D000818:Animals; D005333:Fetus / Q000196:embryology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D053823:Hedgehog Proteins; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011467:Prostate / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism*; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D018976:Insulin-Like Growth Factor Binding Protein 6; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; C000541:cyclopamine