TULP4, a novel E3 ligase gene, participates in neuronal migration as a candidate in schizophrenia

Author:

Bi Yan123ORCID,Ren Decheng123,Yuan Fan123,Zhang Zhou1234,Zhou Daizhan123,Yi Xin123,Ji Lei123,Li Keyi123,Yang Fengping123,Wu Xi123,Li Xingwang123,Xu Yifeng3,Liu Yun5,Wang Peng6,Cai Changqun6,Liu Chuanxin7,Ma Qian8,He Lin123,Shi Yi123,He Guang123

Affiliation:

1. Bio‐X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders Shanghai Jiao Tong University Shanghai China

2. The Collaborative Innovation Center for Brain Science, and Brain Science and Technology Research Center Shanghai Jiao Tong University Shanghai China

3. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center Shanghai Jiao Tong University School of Medicine Shanghai China

4. Burning Rock Biotech Guangzhou China

5. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital Shanghai Jiao Tong University School of Medicine Shanghai China

6. Wuhu Fourth People's Hospital Wuhu China

7. School of Mental Health Jining Medical University Jining China

8. Laboratory Animal Centre Shanghai Jiao Tong University Shanghai China

Abstract

AbstractBackgroundTUB‐like protein 4 (TULP4) is one of the distant members of tubby family proteins, whose function remains largely unknown. In the present study, we intend to identify the role of TULP4 in schizophrenia from human samples and animal models.MethodsWhole‐exome sequencing was used to detect the four schizophrenia families collected. In different cell lines, the effects of identified variants in TULP4 gene on its expression and localization were analyzed. Knockdown models in utero and adult mice were employed to investigate the role of Tulp4 on neuronal migration and schizophrenia‐related behavior. Subsequently, co‐IP assays were used to search for proteins that interact with TULP4 and the effects of mutants on the molecular function of TULP4.ResultsFor the first time, we identified five rare variants in TULP4 from schizophrenia families, of which three significantly reduced TULP4 protein expression. Knockdown the expression of Tulp4 delayed neuronal migration during embryological development and consequently triggered abnormal behaviors in adult mice, including impaired sensorimotor gating and cognitive dysfunction. Furthermore, we confirmed that TULP4 is involved in the formation of a novel E3 ligase through interaction with CUL5‐ELOB/C‐RNF7 and the three deleterious variants affected the binding amount of TULP4 and CUL5 to a certain extent.ConclusionsTogether, we believe TULP4 plays an important role in neurodevelopment and subsequent schizophrenic‐related phenotypes through its E3 ubiquitin ligase function.

Funder

National Basic Research Program of China

National Natural Science Foundation of China

Natural Science Foundation of Shanghai Municipality

Publisher

Wiley

Subject

Pharmacology (medical),Physiology (medical),Psychiatry and Mental health,Pharmacology

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1. From synapse to sensation: the role of circTulp4;Trends in Neurosciences;2024-09

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