PRICKLE2 is a planar cell polarity (PCP) protein that functions as a key regulator of neuronal development and circuit formation. Primary function: PRICKLE2 localizes to the axon initial segment (AIS) and postsynaptic density, where it regulates ANK3/ANKG to modulate microtubule bundling and establish neuronal polarity 1. Mechanism: PRICKLE2 operates within the noncanonical Wnt/PCP signaling pathway, associating with Dishevelled1 (Dvl1) and postsynaptic density protein 95 (PSD-95) to promote neurite outgrowth and regulate synaptic architecture 23. Prickle2 protein levels are negatively regulated through Vangl2-mediated proteasomal degradation via Cullin-1 E3 ubiquitin ligase 4. Disease relevance: Loss-of-function PRICKLE2 variants cause neurodevelopmental disorders characterized by global developmental delay, behavioral difficulties, epilepsy, and autism spectrum disorder features 53. Prickle2 disruption leads to reduced dendrite branching, decreased synapse number, and diminished synaptic currents 3. Clinical significance: Heterozygous PRICKLE2 variants, both de novo and inherited, are associated with neurodevelopmental delay and autism-like phenotypes in humans, suggesting PRICKLE2 as a potential biomarker and therapeutic target for neurological disorders 56.