Arrested pulmonary alveolar cytodifferentiation and defective surfactant synthesis in mice missing the gene for parathyroid hormone-related protein.
Parathyroid hormone-related protein (PTHrP) and PTH/PTHrP receptor expression are developmentally regulated in lung epithelium and adepithelial mesenchyme, respectively. To test the hypothesis that PTHrP is a developmental regulator of terminal airway development, we investigated in vivo and in vitro models of alveolar cytodifferentiation using mice in which the gene encoding PTHrP was ablated by homologous recombination. We have determined that fetal and newborn PTHrP(-/-) lungs showed delayed mesenchymal-epithelial interactions, arrested type II cell differentiation, and reduced surfactant lamellar body formation and pulmonary surfactant production. Embryonic PTHrP(-/-) lung buds cultured in the absence of skeletal constriction or systemic compensating factors also exhibited delayed alveolar epithelial (type II cell) and mesenchymal cytodifferentiation, as well as a > 40% inhibition of surfactant phospholipid production (n = 3-5). Addition of exogenous PTHrP to embryonic PTHrP(-/-) lung cultures normalized interstitial cell morphology and surfactant phospholipid production. The importance of PTHrP as an endogenous regulatory molecule in mammalian lung development is supported by the findings that ablation of PTHrP expression in isolated developing lung is sufficient to disrupt normal development of the alveolar ducts and the centriacinar regions.
Rubin
Lewis P
LP
Department of Pediatrics, Brown Medical School and Women and Infants Hospital, Providence, Rhode Island 02905-2499, USA. lewis_rubin@brown.edu
Kovacs
Christopher S
CS
De Paepe
Monique E
ME
Tsai
Shu-Whei
SW
Torday
John S
JS
Kronenberg
Henry M
HM
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009924:Organ Culture Techniques; D009929:Organ Size; D044162:Parathyroid Hormone-Related Protein / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D010641:Phenotype; D010713:Phosphatidylcholines / Q000096:biosynthesis / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D011663:Pulmonary Surfactants / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D044162:Parathyroid Hormone-Related Protein; D010713:Phosphatidylcholines; D011663:Pulmonary Surfactants; D012333:RNA, Messenger