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AUTS2 Controls Neuronal Lineage Choice Through a Novel PRC1-Independent Complex and BMP Inhibition

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Abstract

Despite a prominent risk factor for Neurodevelopmental disorders (NDD), it remains unclear how Autism Susceptibility Candidate 2 (AUTS2) controls the neurodevelopmental program. Our studies investigated the role of AUTS2 in neuronal differentiation and discovered that AUTS2, together with WDR68 and SKI, forms a novel protein complex (AWS) specifically in neuronal progenitors and promotes neuronal differentiation through inhibiting BMP signaling. Genomic and biochemical analyses demonstrated that the AWS complex achieves this effect by recruiting the CUL4 E3 ubiquitin ligase complex to mediate poly-ubiquitination and subsequent proteasomal degradation of phosphorylated SMAD1/5/9. Furthermore, using primary cortical neurons, we observed aberrant BMP signaling and dysregulated expression of neuronal genes upon manipulating the AWS complex, indicating that the AWS-CUL4-BMP axis plays a role in regulating neuronal lineage specification in vivo. Thus, our findings uncover a sophisticated cellular signaling network mobilized by a prominent NDD risk factor, presenting multiple potential therapeutic targets for NDD.

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To review GEO accession GSE178746, use the following link and enter token (evezqiqwhbqldol), https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE178746.

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Acknowledgements

We would like to thank Dr. Kathleen Mulder for the discussion of the experiments. We thank Dr. Abraham Thomas and the Microscopy Imaging Core for assistance in imaging and Dr. Yuka Imamura and the Genome Sciences Facility for assistance in deep sequencing. The Auts2 mouse strain is a gift from Dr. Danny Reinberg. This work was supported by the following NIH grants: R35GM133496 to Z. Gao; R00AA024837 to J. Stafford; R35ES031707 to Y. Wang. Z. Geng, Q.W., W.M., T.W., J.C., and E.G. conducted the experiments; R.H. and D.D. provided guidance and help on the immunofluorescence analysis; Z. Gao, J.S., and Y.W. designed the experiments; Z.Geng and Z.Gao wrote the paper. All authors contributed to the discussion of the manuscript.

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Authors and Affiliations

  1. Departments of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, 17033, USA

    Zhuangzhuang Geng, Qiang Wang, Jessenia Chavez & Zhonghua Gao

  2. Department of Chemistry, University of California at Riverside, Riverside, CA, 92521, USA

    Weili Miao & Yinsheng Wang

  3. Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, VT, 05405, USA

    Trevor Wolf, Emily Giddings & James Stafford

  4. Department of Dermatology, Penn State College of Medicine, Hershey, PA, 17033, USA

    Ryan Hobbs

  5. Department of Pathology and Laboratory Medicine, Penn State College of Medicine, Hershey, PA, 17033, USA

    David J. DeGraff

  6. Penn State Hershey Cancer Institute, Hershey, PA, 17033, USA

    David J. DeGraff & Zhonghua Gao

  7. The Stem Cell and Regenerative Biology Program, Penn State College of Medicine, Hershey, PA, 17033, USA

    Zhonghua Gao

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  1. Zhuangzhuang Geng
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Correspondence to Zhonghua Gao.

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Geng, Z., Wang, Q., Miao, W. et al. AUTS2 Controls Neuronal Lineage Choice Through a Novel PRC1-Independent Complex and BMP Inhibition. Stem Cell Rev and Rep 19, 531–549 (2023). https://doi.org/10.1007/s12015-022-10459-0

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