PT  - JOURNAL ARTICLE
AU  - Xiaoyun Sun
AU  - Xixia Peng
AU  - Yuqing Cao
AU  - Yan Zhou
AU  - Yuhua Sun
TI  - ADNP promotes neural differentiation by modulating Wnt/β-catenin signaling
AID  - 10.1101/761064
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 761064
4099  - http://biorxiv.org/content/early/2019/09/09/761064.short
4100  - http://biorxiv.org/content/early/2019/09/09/761064.full
AB  - ADNP (Activity Dependent Neuroprotective Protein) is proposed as a neuroprotective protein whose aberrant expression has been frequently linked to neural developmental disorders, including the Helsmoortel-Van der Aa syndrome. However, its role in neural development and pathology remains unclear. Using mESC (mouse embryonic stem cell) directional neural differentiation as a model, we show that ADNP is required for ESC neural induction and neuronal differentiation by maintaining Wnt signaling. Mechanistically, ADNP functions to maintain the proper protein levels of β-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC. Loss of ADNP promotes the formation of the degradation complex and hyperphosphorylation of β-Catenin by GSK3β and subsequent degradation via ubiquitin-proteasome pathway, resulting in down-regulation of key neuroectoderm developmental genes. We further show that ADNP plays key role in cerebellar neuron formation. Finally, adnp gene disruption in zebrafish embryos recapitulates key features of the mouse phenotype, including the reduced Wnt signaling, defective embryonic cerebral neuron formation and the massive neuron death. Thus, our work provides important insights into the role of ADNP in neural development and the pathology of the Helsmoortel-Van der Aa syndrome caused by ADNP gene mutation.