Scientists Reveal Key Role of ADNP in Neural Induction and Differentiation

There is an increased incidence of neurodevelopmental disorders around the world, including the Helsmoortel-Van der Aa syndrome (also called the ADNP syndrome) and autism spectrum disorder (ASD). In China, the number of ASD patients may exceed 10 million, of which approximately 20% are children. The number is increasing 200,000 per year. Patients may exhibit varying degree of neurological dysfunctions, including intelligent, language, behavior and facial development defects, depending on the individual’s genetic background.  

Activity Dependent Neuroprotective Protein (ADNP) is one of the most frequent ASD-associated genes as it is mutated in at least 0.17% of ASD cases. However, the pathology of the Helsmoortel-Van der Aa syndrome caused by ADNP mutation remains unclear.  

A research team led by Prof. SUN Yuhua from Institute of Hydrobiology (IHB) of Chinese Academy of Sciences, has revealed, for the first time, the key role of ADNP in the neural induction and differentiation.    

By making use of embryonic stem cells and zebrafish as model systems, the research group investigated the role of ADNP in embryonic neural development. They found that ADNP is required for proper neural induction by modulating Wnt/β-catenin signaling.  

Mechanistically, ADNP functions to stabilize β-Catenin through binding to its armadillo domain which prevents its interaction with key components of degradation complex - Axin and APC.  

Loss of ADNP leads to hyperphosphorylation of β-Catenin by GSK3β and subsequent degradation via ubiquitin-proteasome pathway, resulting in down-regulation of neuroectoderm developmental genes. 

The study has revealed that ADNP promotes neural differentiation through Wnt/β-catenin signaling pathway by stabilizing β-catenin, explaining why loss of ADNP leads to ASD or neurodevelopmental disorders in children. Thus, the work provides important insights into the role of ADNP in neural development which would be useful for understanding the pathology of the Helsmoortel-Van der Aa syndrome caused by ADNP mutation and treating the disease in the future.  

The study, published in Nature communications on 12 June, 2020, was supported by National Key Research and Development Program (2016YFA0101100), National Natural Science Foundation of China (31671526) to Dr. Yuhua Sun. In the future, Prof. Sun, in collaboration with his colleagues, will establish a primate disease model to further study the pathology of the Helsmoortel-Van der Aa syndrome.