MAPK8IP3 encodes JIP3, a scaffold protein that mediates JNK signaling and regulates axonal transport in neurons. Functionally, JIP3 acts as an adaptor protein within the kinesin-1 complex, promoting anterograde axonal transport of cargo including NTRK2/TRKB and late endosomes 12. JIP3 facilitates axon elongation by activating cofilin through local JNK activation and bridges interactions between NTRK2/TRKB and kinesin light chains, essential for BDNF-triggered signaling 1. The protein also functions in endocytosis regulation, with loss of MAPK8IP3 impairing endocytic uptake in neurons 3. Mechanistically, JIP3 interacts with dynein-dynactin complexes on microtubules, where LIS1 stabilizes complex formation 4. Pathogenic MAPK8IP3 variants cause neurodevelopmental disorder characterized by cognitive impairment, hypotonia, motor delays, microcephaly, corpus callosum thinning, and ataxia 56. Missense mutations (e.g., R578C) act as toxic gain-of-function variants that disrupt JIP3's interactome, increase JNK signaling leading to apoptosis, and impair late endosome transport 2. Compound heterozygous variants cause severe congenital hypotonia mimicking spinal muscular atrophy 7. Missense variants associate with more severe phenotypes than loss-of-function variants 5. These findings indicate MAPK8IP3 is essential for proper neuronal development and axonal transport, with mutations causing significant neurodevelopmental consequences.