Sonic hedgehog signaling regulates Gli3 processing, mesenchymal proliferation, and differentiation during mouse lung organogenesis

Autor: Huimin Zhang, Chin Chiang, Seung Cheol Choi, Yina Li, Ying Litingtung
Rok vydání: 2004
Předmět:
Proliferation
Wnt2 Protein
Mesoderm
Mice
WNT2
Sonic hedgehog
Lung
Regulation of gene expression
Mice
Knockout
biology
Myogenesis
Tbx
Veratrum Alkaloids
Gene Expression Regulation
Developmental
Cell Differentiation
Forkhead Transcription Factors
respiratory system
Hedgehog signaling pathway
DNA-Binding Proteins
medicine.anatomical_structure
Differentiation
embryonic structures
Lung hypoplasia
Signal Transduction
animal structures
Mesenchyme
Kruppel-Like Transcription Factors
Repressor
Neovascularization
Physiologic
Gestational Age
Nerve Tissue Proteins
Proto-Oncogene Proteins c-myc
Zinc Finger Protein Gli3
Culture Techniques
Cyclins
Proto-Oncogene Proteins
GLI3
medicine
Animals
Humans
Hedgehog Proteins
Molecular Biology
Gli3 repressor
Epithelial Cells
Cell Biology
Zebrafish Proteins
Embryo
Mammalian
Foxf1
Wnt Proteins
biology.protein
Cancer research
Trans-Activators
Transcription Factors
Developmental Biology
Zdroj: Developmental Biology. 270(1):214-231
ISSN: 0012-1606
DOI: 10.1016/j.ydbio.2004.03.009
Popis: Lack of Sonic hedgehog (Shh) signaling, mediated by the Gli proteins, leads to severe pulmonary hypoplasia. However, the precise role of Gli genes in lung development is not well established. We show Shh signaling prevents Gli3 proteolysis to generate its repressor forms (Gli3R) in the developing murine lung. In Shh(-/-) or cyclopamine-treated wild-type (WT) lung, we found that Gli3R level is elevated, and this upregulation appears to contribute to defects in proliferation and differentiation observed in the Shh(-/-) mesenchyme, where Gli3 is normally expressed. In agreement, we found Shh(-/-);Gli3(-/-) lungs exhibit enhanced growth potential. Vasculogenesis is also enhanced; in contrast, bronchial myogenesis remains absent in Shh(-/-);Gli3(-/-) compared with Shh(-/-) lungs. Genes upregulated in Shh(-/-);Gli3(-/-) relative to Shh(-/-) lung include Wnt2 and, surprisingly, Foxf1 whose expression has been reported to be Shh-dependent. Cyclins D1, D2, and D3 antibody labelings also reveal distinct expression patterns in the normal and mutant lungs. We found significant repression of Tbx2 and Tbx3, both linked to inhibition of cellular senescence, in Shh(-/-) and partial derepression in Shh(-/-); Gli3(-/-) lungs, while Tbx4 and Tbx5 expressions are less affected in the mutants. Our findings shed light on the role of Shh signaling on Gli3 processing in lung growth and differentiation by regulating several critical genes.
Databáze: OpenAIRE
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