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  • GORAB promotes embryonic lung maturation through antagonizing AKT phosphorylation, versican expression, and mesenchymal cell migration.

GORAB promotes embryonic lung maturation through antagonizing AKT phosphorylation, versican expression, and mesenchymal cell migration.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2020-02-19)
Ying Liu, Xi Chen, Yeon Ja Choi, Ning Yang, Zhongya Song, Elizabeth R Snedecor, Wei Liang, Elaine Lai-Han Leung, Lianfeng Zhang, Chuan Qin, Jiang Chen
ABSTRACT

Embryonic development of the alveolar sac of the lung is dependent upon multiple signaling pathways to coordinate cell growth, migration, and the formation of the extracellular matrix. Here, we identify GORAB as a regulator of embryonic alveolar sac formation as genetically disrupting the Gorab gene in mice resulted in fatal saccular maturation defects characterized by a thickened lung mesenchyme. This abnormality is not associated with impairments in cellular proliferation and death, but aberrantly increased protein kinase B (AKT) phosphorylation, elevated Vcan transcription, and enhanced migration of mesenchymal fibroblasts. Genetically augmenting PDGFRα, a potent activator of AKT in lung mesenchymal cells, recapitulated the alveolar phenotypes, whereas disrupting PDGFRα partially rescued alveolar phenotypes in Gorab-deficient mice. Overexpressing or suppressing Vcan in primary embryonic lung fibroblasts could, respectively, mimic or attenuate alveolar sac-like phenotypes in a co-culture model. These findings suggest a role of GORAB in negatively regulating AKT phosphorylation, the expression of Vcan, and the migration of lung mesenchyme fibroblasts, and suggest that alveolar sac formation resembles a patterning event that is orchestrated by molecular signaling and the extracellular matrix in the mesenchyme.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
7-Aminoactinomycin D, ~97% (HPLC), powder
Sigma-Aldrich
Anti-PDGF-AA Antibody, from rabbit, purified by affinity chromatography
Sigma-Aldrich
Anti-Versican Antibody, a.a. 535-598 of mouse versican, Chemicon®, from rabbit