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Shaggy regulates tissue growth through Hippo pathway in Drosophila

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Abstract

The evolutionarily conserved Hippo pathway coordinates cell proliferation, differentiation and apoptosis to regulate organ growth and tumorigenesis. Hippo signaling activity is tightly controlled by various upstream signals including growth factors and cell polarity, but the full extent to which the pathway is regulated during development remains to be resolved. Here, we report the identification of Shaggy, the homolog of mammalian Gsk3β, as a novel regulator of the Hippo pathway in Drosophila. Our results show that Shaggy promotes the expression of Hippo target genes in a manner that is dependent on its kinase activity. Loss of Shaggy leads to Yorkie inhibition and downregulation of Hippo pathway target genes. Mechanistically, Shaggy acts upstream of the Hippo pathway and negatively regulates the abundance of the FERM domain containing adaptor protein Expanded. Our results reveal that Shaggy is functionally required for Crumbs/Slmb-mediated downregulation of Expanded in vivo, providing a potential molecular link between cellular architecture and the Hippo signaling pathway.

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Acknowledgements

This study was supported by the National Key R&D Program of China (2021YFA0805800, 2020YFA0803202, 2018YFC1003203, 2021YFC2700403), the National Natural Science Foundation of China (31970538, 32000574, 31871452), the Guangzhou Medical University Discipline Construction Funds (Basic Medicine) (JCXKJS2022A02), the 111 Project (D18010), the Local Innovative and Research Teams Project of Guangdong Perl River Talents Program (2017BT01S155), the Special Innovation Projects of Universities in Guangdong Province (2018KTSCX182), the Medical Scientific Research Foundation of Guangdong Province (A2019292), and the Natural Science Foundation of Guangdong Province (2017A030310403). We are grateful to Drs. Duojia Pan, Richard Fehon, Lei Zhang and Daniel Kalderon for kindly sharing reagents. We acknowledge members of the Jiao laboratory for discussions.

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Authors and Affiliations

  1. Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China

    Honggang Wu, Nannan Zhu, Jiyong Liu & Renjie Jiao

  2. State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China

    Honggang Wu, Nannan Zhu, Jiyong Liu & Renjie Jiao

  3. State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Honggang Wu, Nannan Zhu & Renjie Jiao

  4. Women’s Hospital and Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Jun Ma

  5. Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Zhejiang University School of Medicine, Hangzhou, 311121, China

    Jun Ma

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  1. Honggang Wu
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Wu, H., Zhu, N., Liu, J. et al. Shaggy regulates tissue growth through Hippo pathway in Drosophila. Sci. China Life Sci. 65, 2131–2144 (2022). https://doi.org/10.1007/s11427-022-2156-2

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