ASD-related genes, 14-3-3 and ADNP, regulate neuronal morphology during cortical development

Mutations in activity-dependent neuroprotective protein (ADNP) are among the most common causes of autism spectrum disorder (ASD) and cause ADNP syndrome, in which ASD is one of the most prominent symptoms. It is known that Adnp regulates a multitude of cell events during the development of the cortical cortex, including neuronal morphology and functional connectivity. Considering that there are no treatments available for patients with ADNP syndrome, it is essential to investigate ADNP’s roles during development. As a result of the Adnp disruption in the developing cortex, multiple deficits were observed in neuronal morphology, dendritic spine formation, neural connectivity, and neural activity. Furthermore, we demonstrated that Adnp is phosphorylated by PKC and transported into the cytoplasm by a 14-3-3 protein during neuronal differentiation in the cortex. Ultimately, this shuttling mechanism attracts our attention and is also clinically important since the most severe cases of ADNP syndrome are caused by mutations that lead to the retention of ADNP in the nucleus or cytoplasm. Also, we found that Adnp regulates the distribution of microtubule binding protein, MAP6, to microtubules within the cytoplasm. We have thereby demonstrated for the first time that Adnp is phosphorylated by PKC, which facilitates its binding to 14-3-3 during neuronal differentiation. These studies will provide fundamental and transformative insights into the mechanisms underlying ADNP syndrome and offer new perspectives for its treatment.