ADNP promotes neural differentiation by modulating Wnt/β-catenin signaling

Xiaoyun Sun, Xixia Peng, Yuqing Cao, Yan Zhou & Yuhua Sun

Sep 13, 2019

Received Date: 11th August 19

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-vanderAa 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 neural induction and neuronal differentiation by maintaining canonical Wnt signaling. Mechanistically, ADNP functions to maintain β-Catenin levels 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 and defective neural induction. We further show that ADNP plays key role in proper cerebellar Purkinje neuron formation. Finally, adnp gene disruption in zebrafish embryos recapitulates key features of the mouse phenotype, including reduced Wnt signaling and defective embryonic brain neuron formation. Thus, our work provides important insights into the role of ADNP in neural development and the pathology of the Helsmoortel-vanderAa syndrome caused by ADNP gene mutation.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature