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Evidence that SPROUTY2 functions as an inhibitor of mouse embryonic lung growth and morphogenesis.
- Source :
-
Mechanisms of development [Mech Dev] 2001 Apr; Vol. 102 (1-2), pp. 81-94. - Publication Year :
- 2001
-
Abstract
- Experimental evidence is rapidly emerging that the coupling of positive regulatory signals with the induction of negative feedback modulators is a mechanism of fine regulation in development. Studies in Drosophila and chick have shown that members of the SPROUTY family are inducible negative regulators of growth factors that act through tyrosine kinase receptors. We and others have shown that Fibroblast Growth Factor 10 (FGF10) is a key positive regulator of lung branching morphogenesis. Herein, we provide direct evidence that mSprouty2 is dynamically expressed in the peripheral endoderm in embryonic lung and is downregulated in the clefts between new branches at E12.5. We found that mSprouty2 was expressed in a domain restricted in time and space, adjacent to that of Fgf10 in the peripheral mesenchyme. By E14.5, Fgf10 expression was restricted to a narrow domain of mesenchyme along the extreme edges of the individual lung lobes, whereas mSprouty2 was most highly expressed in the subjacent epithelial terminal buds. FGF10 beads upregulated the expression of mSprouty2 in adjacent epithelium in embryonic lung explant culture. Lung cultures treated with exogenous FGF10 showed greater branching and higher levels of mSpry2 mRNA. Conversely, Fgf10 antisense oligonucleotides reduced branching and decreased mSpry2 mRNA levels. However, treatment with exogenous FGF10 or antisense Fgf10 did not change Shh and FgfR2 mRNA levels in the lungs. We investigated Sprouty2 function during lung development by two different but complementary approaches. The targeted overexpression of mSprouty2 in the peripheral lung epithelium in vivo, using the Surfactant Protein C promoter, resulted in a low level of branching, lung lobe edges abnormal in appearance and the inhibition of epithelial proliferation. Transient high-level overexpression of mSpry2 throughout the pulmonary epithelium by intra-tracheal adenovirus microinjection also resulted in a low level of branching. These results indicate for the first time that mSPROUTY2 functions as a negative regulator of embryonic lung morphogenesis and growth.
- Subjects :
- Adenoviridae genetics
Animals
Cell Division
Epithelial Cells metabolism
Fibroblast Growth Factor 10
Fibroblast Growth Factors metabolism
Genotype
Humans
Lung cytology
Mesoderm metabolism
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Transgenic
Oligonucleotides, Antisense
Organ Culture Techniques
Plasmids metabolism
Proliferating Cell Nuclear Antigen metabolism
Promoter Regions, Genetic
Protein Structure, Tertiary
Proteolipids genetics
Pulmonary Surfactants genetics
RNA, Messenger metabolism
RNA-Directed DNA Polymerase metabolism
Recombinant Proteins metabolism
Reverse Transcriptase Polymerase Chain Reaction
Time Factors
Up-Regulation
Lung embryology
Lung metabolism
Nerve Tissue Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0925-4773
- Volume :
- 102
- Issue :
- 1-2
- Database :
- MEDLINE
- Journal :
- Mechanisms of development
- Publication Type :
- Academic Journal
- Accession number :
- 11287183
- Full Text :
- https://doi.org/10.1016/s0925-4773(01)00286-6