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Title: Differential regulation of Gli proteins by Sufu in the lung affects PDGF signaling and myofibroblast development

Author
item LIN, CHUWEN - University Of California
item CHEN, MIAO-HSUEH - Children'S Nutrition Research Center (CNRC)
item YAO, ERICA - University Of California
item SONG, HAI - University Of California
item GACAYAN, RHODORA - University Of California
item HUI, CHI-CHUNG - University Of Toronto
item CHUANG, PAO-TIEN - University Of California

Submitted to: Developmental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/20/2014
Publication Date: 6/2/2014
Citation: Lin, C., Chen, M., Yao, E., Song, H., Gacayan, R., Hui, C., Chuang, P. 2014. Differential regulation of Gli proteins by Sufu in the lung affects PDGF signaling and myofibroblast development. Developmental Biology. 392(2):324-333.

Interpretive Summary: The Hedgehog signaling pathway, which is regulated by nutrients, controls the growth of the lung during pregnancy. In this study, we showed that mice lose lung myofibroblast cells; a group of cells that regulate contraction and air exchange of the lungs when Hedgehog signaling is abnormally activated in pregnant mice. Because mutations in human Hedgehog pathway components often result in birth defects in several organs, including the lung, the knowledge from this study will help us to understand the causes of these birth defects.

Technical Abstract: Mammalian Hedgehog (Hh) signaling relies on three Gli transcription factors to mediate Hh responses. This process is controlled in part by a major negative regulator, Sufu, through its effects on Gli protein level, distribution and activity. In this report, we showed that Sufu regulates Gli1 protein levels by antagonizing Numb/Itch. Otherwise, Numb/Itch would induce Gli1 protein degradation. This is in contrast to inhibition of Spop-mediated degradation of Gli2/3 by Sufu. Thus, controlling protein levels of all three Gli genes by Sufu is a conserved mechanism to modulate Hh responses albeit via distinct pathways. These findings in cell-based assays were further validated "in vivo". In analyzing how Sufu controls Gli proteins in different tissues, we discovered that loss of "Sufu" in the lung exerts different effects on Hh target genes. Hh targets "Ptch1/Hhip" are upregulated in "Sufu"-deficient lungs, consistent with Hh pathway activation. Surprisingly, protein levels of Hh target Gli1 are reduced. We also found that myofibroblasts are absent from many prospective alveoli of "Sufu"-deficient lungs. Myofibroblast development is dependent on PDGF signaling. Interestingly, analysis of the "Pdgfra" promoter revealed a canonical Gli-binding site where Gli1 resides. These studies support a model in which loss of "Sufu" contributes to compromised "Pdgfra" activation and disrupts myofibroblast development in the lung. Our work illustrates the unappreciated complexity of Hh responses where distinct Hh targets could respond differently depending on the availability of Gli proteins that control their expression.