Dysregulation of the Wnt/β-catenin signaling pathway via Rnf146 upregulation in a VPA-induced mouse model of autism spectrum disorder

Gaeun Park, Wooyoung Eric Jang, Seoyeon Kim, Edson Luck Gonzales, Jungeun Ji, Seunghwan Choi, Yujin Kim, Ji Hwan Park, Hazara Begum Mohammad, Geul Bang, Minkyung Kang, Soobin Kim, Se Jin Jeon, Jin Young Kim, Kwang Pyo Kim, Chan Young Shin, Joon Yong An, Min Sik Kim, Yong Seok Lee

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with impaired social behavior and communication, repetitive behaviors, and restricted interests. In addition to genetic factors, environmental factors such as prenatal drug exposure contribute to the development of ASD. However, how those prenatal factors induce behavioral deficits in the adult stage is not clear. To elucidate ASD pathogenesis at the molecular level, we performed a high-resolution mass spectrometry-based quantitative proteomic analysis on the prefrontal cortex (PFC) of mice exposed to valproic acid (VPA) in utero, a widely used animal model of ASD. Differentially expressed proteins (DEPs) in VPA-exposed mice showed significant overlap with ASD risk genes, including differentially expressed genes from the postmortem cortex of ASD patients. Functional annotations of the DEPs revealed significant enrichment in the Wnt/β-catenin signaling pathway, which is dysregulated by the upregulation of Rnf146 in VPA-exposed mice. Consistently, overexpressing Rnf146 in the PFC impaired social behaviors and altered the Wnt signaling pathway in adult mice. Furthermore, Rnf146-overexpressing PFC neurons showed increased excitatory synaptic transmission, which may underlie impaired social behavior. These results demonstrate that Rnf146 is critical for social behavior and that dysregulation of Rnf146 underlies social deficits in VPA-exposed mice.

Original languageEnglish
Pages (from-to)1783-1794
Number of pages12
JournalExperimental and Molecular Medicine
Issue number8
Publication statusPublished - 2023 Aug

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry


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