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

Zhuangzhuang Geng, Qiang Wang, Weili Miao, Trevor Wolf, Jessenia Chavez, Emily Giddings, Ryan Hobbs, David J. DeGraff, Yinsheng Wang, James Stafford, Zhonghua Gao

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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. Graphical Abstract: [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)531-549
Number of pages19
JournalStem Cell Reviews and Reports
Volume19
Issue number2
DOIs
StatePublished - Feb 2023

All Science Journal Classification (ASJC) codes

  • Cell Biology
  • Cancer Research

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