Leever, N. | bioRxiv Science

bioRxiv2026

SARM1 is required for macrophage immunophenotype switching that is essential for nerve repair

SARM1 is a key executor of Wallerian degeneration in axons. Global knockout of sarm1 in mice delays degeneration for several weeks. Recently, we reported that Schwann cell reprogramming, inflammation, and axon regeneration are also delayed in these animals. Several studies have also indicated that SARM1 has essential regulatory functions in macrophages (M{phi}). However, the role of SARM1 in M{phi} in the context of peripheral nerve injury remains unknown. Here, we report that loss of sarm1 impairs splenic M{phi} from adopting immunological stimuli driven immunophenotypes in culture. Through a combination of cell culture, Western blotting, gene expression analysis, in vivo injection of M{phi} into sciatic nerves, and generation of cell specific sarm1 conditional knockout mouse lines, we found that SARM1 is required for proper immunophenotypes in M{phi}. Loss of sarm1 in macrophages increases neurite length of sensory neurons in culture but delays regeneration in a model of peripheral nerve injury. We identified dysregulation of several inflammatory and anti-inflammatory immunological stimuli pathways and altered regulation of both iNOS and Arginase-1 in Sarm1-/- M{phi}. In culture, Sarm1-/- M{phi} display difficulty phagocytosing and clearing myelin debris and this was recapitulated in vivo with a M{phi} specific sarm1 knockout line. Generation of M{phi} and neuronal sarm1 conditional knockout mice further indicated that SARM1 is required in both cell types for an efficient response to peripheral nerve injury. This study provides the first evidence that SARM1 signaling in M{phi} is required for injury induced inflammation, degeneration, and axon regeneration.

neuroscience↗

bioRxiv2025

LIS1 is critical for axon integrity in adult mice

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 knockout (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 knockout 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. Significance StatementA healthy nervous system requires that proper brain wiring is maintained throughout the life of the animal. Connectivity often involves the long axons of projection neurons. Some axons drive cognition, others contribute to sensory and motor systems, while still others subserve vitally important cardiorespiratory processes. We show that LIS1, a protein linked to congenital brain abnormalities, also plays a crucial role in fully developed projection neurons in the adult mouse. LIS1 depletion from these cells causes severe axonal degeneration resembling the Wallerian degeneration that occurs in response to nerve injury. Because LIS1 regulates dynein, and because defective dynein can cause neurodegenerative disorders in humans, our study suggests that drugs targeting Wallerian degeneration may have therapeutic potential for dynein-related diseases.

neuroscience↗