DEFECT IN SYNAPTIC VESICLE PRECURSOR TRANSPORT AND NEURONAL CELL-DEATH IN KIF1A MOTOR PROTEIN-DEFICIENT MICE

The nerve axon is a good model system for studying the molecular mecha nism of organelle transport in cells. Recently, the new kinesin superf amily pro teins (KIFs) have been identified as candidate motor protein s involved in organelle transport. Among them KIF1A, a murine homologu e of zinc-104 gene of Cae-norhabditis elegans, is a unique monomeric n euron-specific microtubule plus end-directed motor and has been propos ed as a transporter of synaptic vesicle pre- cursors (Okada, Y., H. Ya mazaki, Y. Sekine-Aizawa, and N. Hirokawa. 1995. Cell. 81:769-780), To elucidate the function of KIF1A in vivo, we disrupted the KIF1A gene in mice. KIF1A mutants died mostly within a day after birth showing mo tor and sensory disturbances. In the nervous systems of these mutants, the transport of synaptic vesicle precursors showed a specific and si gnificant decrease. Consequently, synaptic vesicle density decreased d ramatically, and clusters of clear small vesicles accumulated in the c ell bodies. Furthermore, marked neuronal degeneration and death occurr ed both in KIF1A mutant mice and in cultures of mutant neurons. The ne uronal death in cultures was blocked by coculture with wild-type neuro ns or exposure to a low concentration of glutamate. These results in c ultures suggested that the mutant neurons might not sufficiently recei ve afferent stimulation, such as neuronal contacts or neurotransmissio n, resulting in cell death. Thus, our results demonstrate that KIF1A t ransports a synaptic vesicle precursor and that KIF1A-mediated axonal transport plays a critical role in viability, maintenance, and functio n of neurons, particularly mature neurons.