Gremlin negatively modulates BMP-4 induction of embryonic mouse lung branching morphogenesis.
Bone morphogenetic protein-4 (BMP-4) is a key morphogen for embryonic lung development that is expressed at high levels in the peripheral epithelium, but the mechanisms that modulate BMP-4 function in early mouse lung branching morphogenesis are unclear. Here, we studied the BMP-4 antagonist Gremlin, which is a member of the DAN family of BMP antagonists that can bind and block BMP-2/4 activity. The expression level of gremlin in embryonic mouse lungs is highest in the early embryonic pseudoglandular stage [embryonic days (E) 11.5-14.5] and is reduced during fetal lung maturation (E18.5 to postnatal day 1). In situ hybridization indicates that gremlin is diffusely expressed in peripheral lung mesenchyme and epithelium, but relatively high epithelial expression occurs in branching buds at E11.5 and in large airways after E16.5. In E11.5 lung organ culture, we found that exogenous BMP-4 dramatically enhanced peripheral lung epithelial branching morphogenesis, whereas reduction of endogenous gremlin expression with antisense oligonucleotides achieved the same gain-of-function phenotype as exogenous BMP-4, including increased epithelial cell proliferation and surfactant protein C expression. On the other hand, adenoviral overexpression of gremlin blocked the stimulatory effects of exogenous BMP-4. Therefore, our data support the hypothesis that Gremlin is a physiologically negative regulator of BMP-4 in lung branching morphogenesis.
Shi
W
W
Developmental Biology Program, Department of Surgery, Childrens Hospital Los Angeles Research Institute, Los Angeles, California 90027, USA.
Zhao
J
J
Anderson
K D
KD
Warburton
D
D
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D009024:Morphogenesis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009924:Organ Culture Techniques; D009928:Organ Specificity; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D011506:Proteins; D012333:RNA, Messenger; C525810:Bmp4 protein, mouse; C113178:Grem1 protein, mouse