Up-regulation of fetal rat lung parathyroid hormone-related protein gene regulatory network down-regulates the Sonic Hedgehog/Wnt/betacatenin gene regulatory network.
Lung development depends on endodermal Sonic Hedgehog (Shh) signaling to mesodermal Wingless/int/beta catenin (Wnt/betacatenin), followed by parathyroid hormone-related protein (PTHrP) signaling from endoderm to mesoderm. Fluid distension of fetal rat lung explants up-regulates PTHrP signaling and down-regulates Shh/Wnt/betacatenin signaling, marked by decreases in Patched, Gli, Frizzled, and Dishevelled, inducing fibroblast triglyceride uptake, type II cell saturated phosphatidylcholine, and surfactant protein-B expression. Bumetanide, which inhibits fluid distension, blocked down-regulation of the Shh/Wnt/betacatenin pathway and up-regulation of the PTHrP pathway, whereas PTHrP (1-34, 5 x 10(-7) M) treatment overcame bumetanide inhibition, and the PTHrP receptor antagonist PTHrP (7-34) amide (5 x 10(-6) M) mimicked bumetanide, indicating that PTHrP signaling mediates fluid distension-induced alveolar differentiation. Fetal rat lung explant automaturation was characterized by decreased Wnt/betacatenin signaling and increased PTHrP/PTHrP receptor signaling, up-regulating fibroblast-specific adipocyte differentiation related protein (ADRP) and peroxisome proliferator-activated receptor gamma. Wnt/betacatenin agonists (LiCl or SB415268) maintained Shh/Wnt/betacatenin signaling, blocking spontaneous up-regulation of the PTHrP pathway, whereas PTHrP or cAMP down-regulated Shh/Wnt/betacatenin signaling and stimulated PTHrP signaling for fibroblast and type II cell differentiation. This is the first evidence that alveolar fluid distension is an organizing principle for PTHrP signaling down-regulation of the Shh/Wnt/betacatenin pathway.
Torday
John S
JS
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, California 90502, USA. jtorday@labiomed.org
Rehan
Virender K
VK
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002034:Bumetanide / Q000494:pharmacology; D015536:Down-Regulation; D005333:Fetus / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D008168:Lung / Q000254:growth & development* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics*; D000070780:Perilipin-2; D010713:Phosphatidylcholines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000235:genetics*; D014280:Triglycerides / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics*
D053823:Hedgehog Proteins; D008565:Membrane Proteins; D044162:Parathyroid Hormone-Related Protein; D000070780:Perilipin-2; D010713:Phosphatidylcholines; C000602984:Plin2 protein, rat; D015534:Trans-Activators; D014280:Triglycerides; D051153:Wnt Proteins; D051176:beta Catenin; D002034:Bumetanide