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AUTS2 forms a novel complex to recruit CUL4 E3 for BMP inhibition and neural differnetiation

ABSTRACT: Neurodevelopmental disorders (NDD) present a great challenge for medicine due to their complicated etiology and diverse genetic lesions. Although many risk genes have been identified, we know little about their mechanistic impact on NDD pathogenesis, including that of a prominent risk factor, Autism Susceptibility Candidate 2 (AUTS2). Disruptions of AUTS2 have been frequently observed in NDD patients, but it remains unclear how AUTS2 controls the neurodevelopmental program. Our studies investigated the role of AUTS2 in neuronal differentiation and discovered that AUTS2, together with WDR68 and SKI, form 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 through the recruitment of the CUL4 E3 ubiquitin ligase complex to mediate poly-ubiquitination and subsequent proteasomal degradation of phosphorylated SMAD1/5/9. Using primary cortical neurons from Auts2 deficient mice, we also observed aberrant BMP signaling and dysregulated expression of neuronal genes, indicating that the AWS-CUL4-BMP axis plays a role in regulating neuronal lineage specification in vivo. Our findings uncover a sophisticated cellular signaling network, mobilized by a prominent NDD risk factor, presenting multiple potential therapeutic targets for NDD.

ORGANISM(S): Mus musculus

PROVIDER: GSE178746 | GEO | 2022/12/01

REPOSITORIES: GEO

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