2026/01/28 by Federico Miozzo, Annalaura Zambrano Avendano, Maria Giuseppa Caso +5 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Axon Guidance and Neuronal Signaling #Neuroscience and Neuropharmacology Research #Wnt/β-catenin signaling in development and cancer
paper · pdf · doi:10.3389/fncel.2025.1736960
openalex publication_date 2026/01/28 · openalex created_date 2026/01/29 · openalex updated_date 2026/08/01
Protocadherins are key regulators of neurodevelopment and synaptic function, acting not only as adhesion molecules but also as synaptic hubs for intracellular signaling. Here, we uncover a novel activity-dependent signaling pathway for Pcdh9 , a protocadherin linked to Autism Spectrum Disorder and Major Depressive Disorder. By combining biochemical and immunohistochemistry approaches on neuronal cultures, we show that neuronal activity triggers Matrix Metalloproteases (MMP)-dependent cleavage of PCDH9, generating a C-terminal fragment (CTF) that translocates to the nucleus. PCDH9 CTF overexpression promotes dendritic growth, increases spine density, and concomitantly strengthens excitatory synaptic transmission. These findings identify PCDH9 CTF as a novel activity-dependent signaling molecule that links synaptic activity to structural remodeling and functional modulation, suggesting a new mechanism by which synaptic activity shapes neuronal properties.