Title : ADNP regulates cortical development: Mechanism of ADNP syndrome/autism
Abstract:
Activity-dependent neuroprotective protein (ADNP) is essential for cortical development. Heterozygous pathogenic ADNP variants cause Helsmoortel-Van der Aa syndrome (aka ADNP syndrome), a neurodevelopmental disorder that commonly includes intellectual disability, delayed speech and motor development, and autism spectrum disorder. ADNP acts in distinct cellular compartments. In the nucleus, full-length ADNP participates in chromatin remodeling and transcriptional regulation. In the cytoplasm, ADNP interacts with microtubule-regulatory proteins and helps regulate neurite initiation, axonal growth, dendritic development, and synapse formation. The mechanism coordinating the nuclear and cytoplasmic functions of ADNP during neuronal development remains unclear.
Our studies examine 14-3-3 proteins, particularly 14-3-3ε, as regulators of ADNP nucleocytoplasmic shutling. 14-3-3 proteins bind phosphorylated target proteins and can regulate protein localization, stability, and molecular interactions. We propose that binding to 14-3-3 promotes the redistribution of ADNP from the nucleus to the cytoplasm or retains ADNP in the cytoplasm, increasing the cytoplasmic pool of ADNP available for cytoskeletal regulation. Biochemical and cellular analyses indicate that ADNP associates with 14-3-3 in developing cortical neurons. Reduced ADNP alters neurite number, axonal growth, and dendritic development, indicating that both ADNP expression level and subcellular localization affect neuronal morphogenesis.
This presentation will integrate molecular, cellular, and developmental findings into a model in which 14-3-3-dependent nuclear-to-cytoplasmic shutling coordinates ADNP-mediated transcriptional regulation with microtubule-dependent neuronal development. Pathogenic ADNP variants may disrupt 14-3-3 binding, alter ADNP localization, or reduce the cytoplasmic pool of ADNP. These changes could impair cortical development, including neurite formation, spine/synapse formation, and circuit formation, and contribute to the neurological features of ADNP syndrome. Determining how 14-3-3 regulates ADNP localization may identify specific molecular steps for therapeutic investigation.
