TY - JOUR
T1 - AUTS2 Controls Neuronal Lineage Choice Through a Novel PRC1-Independent Complex and BMP Inhibition
AU - Geng, Zhuangzhuang
AU - Wang, Qiang
AU - Miao, Weili
AU - Wolf, Trevor
AU - Chavez, Jessenia
AU - Giddings, Emily
AU - Hobbs, Ryan
AU - DeGraff, David J.
AU - Wang, Yinsheng
AU - Stafford, James
AU - Gao, Zhonghua
N1 - Funding Information:
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.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2023/2
Y1 - 2023/2
N2 - 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.]
AB - 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.]
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U2 - 10.1007/s12015-022-10459-0
DO - 10.1007/s12015-022-10459-0
M3 - Article
C2 - 36258139
AN - SCOPUS:85140122480
SN - 2629-3269
VL - 19
SP - 531
EP - 549
JO - Stem Cell Reviews and Reports
JF - Stem Cell Reviews and Reports
IS - 2
ER -