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Development, Vol 124, Issue 1 53-63, Copyright © 1997 by Company of Biologists


JOURNAL ARTICLES

Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis

S Bellusci, Y Furuta, MG Rush, R Henderson, G Winnier and BL Hogan
Department of Cell Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2175, USA.

Branching morphogenesis of the embryonic lung requires interactions between the epithelium and the mesenchyme. Previously, we reported that Sonic hedgehog (Shh) transcripts are present in the epithelium of the developing mouse lung, with highest levels in the terminal buds. Here, we report that transcripts of mouse patched (Ptc), the homologue of a Drosophila gene encoding a putative transmembrane protein required for hedgehog signaling, are expressed at high levels in the mesenchyme adjacent to the end buds. To investigate the function of SHH in lung development, Shh was overexpressed throughout the distal epithelium, using the surfactant protein-C (SP-C)-enhancer/promoter. Beginning around 16.5 dpc, when Shh and Ptc RNA levels are normally both declining, this treatment caused an increase in the ratio of interstitial mesenchyme to epithelial tubules in transgenic compared to normal lungs. Transgenic newborn mice die soon after birth. Histological analysis of the lungs at the light and electron microscope level shows an abundance of mesenchyme and the absence of typical alveoli. In vivo BrdU labeling indicates that Shh overexpression results in increased mesenchymal and epithelial cell proliferation at 16.5 and 17.5 dpc. However, analysis of CC-10 and SP-C expression reveals no significant inhibition in the differentiation of proximal and distal epithelial cells. The expression of genes potentially regulated by SHH was also examined. No difference could be observed between transgenic and control lungs in either the level or distribution of Bmp4, Wnt2 and Fgf7 RNA. By contrast, Ptc is clearly upregulated in the transgenic lung. These results thus establish a role for SHH in lung morphogenesis, and suggest that SHH normally regulates lung mesenchymal cell proliferation in vivo.
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R. Mollard and M. Dziadek
A Correlation between Epithelial Proliferation Rates, Basement Membrane Component Localization Patterns, and Morphogenetic Potential in the Embryonic Mouse Lung
Am. J. Respir. Cell Mol. Biol., July 1, 1998; 19(1): 71 - 82.
[Abstract] [Full Text]


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Genes Dev.Home page
M. Treier, A. S. Gleiberman, S. M. O'Connell, D. P. Szeto, J. A. McMahon, A. P. McMahon, and M. G. Rosenfeld
Multistep signaling requirements for pituitary organogenesis in vivo
Genes & Dev., June 1, 1998; 12(11): 1691 - 1704.
[Abstract] [Full Text]


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Genes Dev.Home page
M. Hebrok, S. K. Kim, and D. A. Melton
Notochord repression of endodermal Sonic hedgehog permits pancreas development
Genes & Dev., June 1, 1998; 12(11): 1705 - 1713.
[Abstract] [Full Text]


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DevelopmentHome page
J. Kohtz, D. Baker, G Corte, and G Fishell
Regionalization within the mammalian telencephalon is mediated by changes in responsiveness to Sonic Hedgehog
Development, January 12, 1998; 125(24): 5079 - 5089.
[Abstract] [PDF]


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DevelopmentHome page
L Laforest, C. Brown, G Poleo, J Geraudie, M Tada, M Ekker, and M. Akimenko
Involvement of the sonic hedgehog, patched 1 and bmp2 genes in patterning of the zebrafish dermal fin rays
Development, January 11, 1998; 125(21): 4175 - 4184.
[Abstract] [PDF]


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DevelopmentHome page
M Weinstein, X Xu, K Ohyama, and C. Deng
FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung
Development, January 9, 1998; 125(18): 3615 - 3623.
[Abstract] [PDF]


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DevelopmentHome page
D. Roberts, D. Smith, D. Goff, and C. Tabin
Epithelial-mesenchymal signaling during the regionalization of the chick gut
Development, January 8, 1998; 125(15): 2791 - 2801.
[Abstract] [PDF]


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DevelopmentHome page
H Ohmichi, U Koshimizu, K Matsumoto, and T Nakamura
Hepatocyte growth factor (HGF) acts as a mesenchyme-derived morphogenic factor during fetal lung development
Development, January 4, 1998; 125(7): 1315 - 1324.
[Abstract] [PDF]


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DevelopmentHome page
D Duprez, C Fournier-Thibault, and N Le Douarin
Sonic Hedgehog induces proliferation of committed skeletal muscle cells in the chick limb
Development, January 2, 1998; 125(3): 495 - 505.
[Abstract] [PDF]


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DevelopmentHome page
S Bellusci, J Grindley, H Emoto, N Itoh, and B. Hogan
Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung
Development, January 12, 1997; 124(23): 4867 - 4878.
[Abstract] [PDF]


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DevelopmentHome page
P Lindahl, L Karlsson, M Hellstrom, S Gebre-Medhin, K Willetts, J. Heath, and C Betsholtz
Alveogenesis failure in PDGF-A-deficient mice is coupled to lack of distal spreading of alveolar smooth muscle cell progenitors during lung development
Development, January 10, 1997; 124(20): 3943 - 3953.
[Abstract] [PDF]


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Cold Spring Harb Symp Quant BiolHome page
B.L.M. Hogan, J. Grindley, S. Bellusci, N.R. Dunn, H. Emoto, and N. Itoh
Branching Morphogenesis of the Lung: New Models for a Classical Problem
Cold Spring Harb Symp Quant Biol, January 1, 1997; 62(0): 249 - 256.
[Abstract] [PDF]


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Cold Spring Harb Symp Quant BiolHome page
I. Thesleff and J. Jernvall
The Enamel Knot: A Putative Signaling Center Regulating Tooth Development
Cold Spring Harb Symp Quant Biol, January 1, 1997; 62(0): 257 - 267.
[Abstract] [PDF]


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Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
L. Lim, V. V. Kalinichenko, J. A. Whitsett, and R. H. Costa
Fusion of lung lobes and vessels in mouse embryos heterozygous for the forkhead box f1 targeted allele
Am J Physiol Lung Cell Mol Physiol, May 1, 2002; 282(5): L1012 - L1022.
[Abstract] [Full Text] [PDF]




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