| First Author | Matoo S | Year | 2026 |
| Journal | J Neurosci | Volume | 46 |
| Issue | 20 | PubMed ID | 41997870 |
| Mgi Jnum | J:390811 | Mgi Id | MGI:8399178 |
| Doi | 10.1523/JNEUROSCI.1971-25.2026 | Citation | Matoo S, et al. (2026) LIS1 Is Critical for Axon Integrity in Adult Mice. J Neurosci 46(20) |
| abstractText | Mutations in human LIS1 cause lissencephaly, a severe developmental brain malformation. Although most studies focus on development, LIS1 is also expressed in adult mouse tissues. We previously induced LIS1 knock-out (iKO) in adult mice using a Cre-Lox approach with an actin promoter driving CreERT2 expression. This proved to be rapidly lethal, with evidence pointing toward nervous system dysfunction. CreERT2 activity was observed in astrocytes, brainstem and spinal motor neurons, and axons and Schwann cells in the sciatic and phrenic nerves, suggesting dysfunctional cardiorespiratory and motor circuits. However, it is unclear how LIS1 knock-out in these different cell types contributes to the lethal phenotype. We now report that LIS1 depletion from astrocytes is not lethal to mice (male or female), although glial fibrillary protein (GFAP) expression is increased in all LIS1-depleted astrocytes. In contrast, LIS1 depletion from projection neurons causes motor deficits and rapid lethality in both males and females. 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 (dynein, hereafter), a microtubule motor whose disruption can cause both cortical malformations and later-onset neurodegenerative diseases, such as Charcot-Marie-Tooth 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. |
