Abstract
ADNP (Activity Dependent Neuroprotective Protein) is a neuroprotective protein whose aberrant expression has been frequently linked to neural developmental disorders, including the Helsmoortel-Van der Aa syndrome (also called the ADNP syndrome). However, its role in neural development and pathology remains unclear. Here, we show that ADNP is required for neural induction and differentiation by enhancing Wnt signaling. Mechanistically, ADNP functions to stabilize 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 β-Catenin degradation via ubiquitin-proteasome pathway, resulting in down-regulation of key neuroectoderm developmental genes. In addition, adnp gene disruption in zebrafish leads to defective neurogenesis and reduced Wnt signaling. 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.
Highlights
ADNP (Activity Dependent Neuroprotective Protein) is a neuroprotective protein whose aberrant expression has been frequently linked to neural developmental disorders, including the Helsmoortel-Van der Aa syndrome
We found that loss of ADNP had little effect on the mRNA levels of Ctnnb1 gene which encodes β-catenin in ESCs
During ESC differentiation toward a neural fate, the cellular localization of ADNP was shifted from predominantly nuclear to cytoplasmic. This nucleus-cytoplasm translocation during neural differentiation was observed by Dr Gozes’s group using P19 cell line21. These observations suggest that the intra-cellular localization of ADNP is tightly regulated during neural induction, and/or that ADNP plays an important role in the cytoplasm for the induction, maintenance and maturation of neural cell types
Summary
ADNP (Activity Dependent Neuroprotective Protein) is a neuroprotective protein whose aberrant expression has been frequently linked to neural developmental disorders, including the Helsmoortel-Van der Aa syndrome ( called the ADNP syndrome). 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. E8.5 Adnp mutant embryos exhibit ectopic expression of pluripotency gene Pou5f1 and reduced expression of neural developmental gene Pax in the anterior neural plate These observations strongly suggest that ADNP plays essential roles during neurogenesis of mouse embryos. De novo mutations in ADNP gene have recently been linked to neural developmental disorders, including the Helsmoortel-Van der Aa syndrome. ADNP functions to stabilize βCatenin through binding to its armadillo domain which prevents its interaction with key components of degradation complex: Axin and APC. This 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
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