LIS1 is critical for axon integrity in adult mice

Mutations in LIS1 cause lissencephaly, a severe developmental brain malformation in humans. Altered proliferation and migration of neural precursors during brain development have been documented in mouse models. Although most studies focus on development, LIS1 is also expressed in adult mouse tissues. We previously induced LIS1 knockout (iKO) in adult mice using a Cre-Lox approach with an actin promoter driving CreERT2 expression. This proved to be rapidly lethal, but death occurred before tamoxifen-induced CreERT2 activity became widespread. The heart showed the highest level of CreERT2 activity, but heart-specific LIS1 depletion did not affect survival, ruling out a cardiac-based etiology. CreERT2 activity was observed in many astrocytes and some neurons in the brain suggesting that the defect could be related to defective cardiorespiratory circuits. We now report that LIS1 depletion from astrocytes is not lethal to mice although glial fibrillary protein (GFAP) expression is increased in LIS1 depleted astrocytes. In contrast, LIS1 depletion from projection neurons causes motor deficits and rapid lethality. This is accompanied by progressive, widespread axonal degeneration along the entire length of both motor and sensory axons. Interestingly, sensory neurons harvested from iKO mice initially extend axons in culture but soon develop axonal swellings and fragmentation, indicating axonal degeneration. LIS1 is a prominent regulator of cytoplasmic dynein 1, a microtubule motor whose disruption can cause both cortical malformations and later-onset neurodegenerative disease. Our results raise the possibility that LIS1 depletion, through disruption of dynein function in mature axons, may lead to Wallerian-like axon degeneration without traumatic nerve injury.