A novel function for the protein tyrosine phosphatase Shp2 during lung branching morphogenesis.
Branching morphogenesis of many organs, including the embryonic lung, is a dynamic process in which growth factor mediated tyrosine kinase receptor activation is required, but must be tightly regulated to direct ramifications of the terminal branches. However, the specific regulators that modulate growth factor signaling downstream of the tyrosine kinase receptor remain to be determined. Herein, we demonstrate for the first time an important function for the intracellular protein tyrosine phosphatase Shp2 in directing embryonic lung epithelial morphogenesis. We show that Shp2 is specifically expressed in embryonic lung epithelial buds, and that loss of function by the suppression of Shp2 mRNA expression results in a 53% reduction in branching morphogenesis. Furthermore, by intra-tracheal microinjection of a catalytically inactive adenoviral Shp2 construct, we provide direct evidence that the catalytic activity of Shp2 is required for proper embryonic lung branch formation. We demonstrate that Shp2 activity is required for FGF10 induced endodermal budding. Furthermore, a loss of Shp2 catalytic activity in the embryonic lung was associated with a reduction in ERK phosphorylation and epithelial cell proliferation. However, epithelial cell differentiation was not affected. Our results show that the protein tyrosine phosphatase Shp2 plays an essential role in modulating growth factor mediated tyrosine kinase receptor activation in early embryonic lung branching morphogenesis.
Tefft
Denise
D
Developmental Biology Program, Department of Surgery, USC Keck School of Medicine and the Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
De Langhe
Stijn P
SP
Del Moral
Pierre-Marie
PM
Sala
Frederic
F
Shi
Wei
W
Bellusci
Saverio
S
Warburton
David
D
D000256:Adenoviridae; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001980:Bronchi / Q000196:embryology*; D002384:Catalysis; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D004848:Epithelium / Q000502:physiology; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005822:Genetic Vectors; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009024:Morphogenesis / Q000502:physiology*; D016376:Oligonucleotides, Antisense; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D017931:DNA Primers; D018076:DNA, Complementary; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D005346:Fibroblast Growth Factors; D020928:Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse