Importin Functions in Physiology and Disease
Importins, nuclear import transport factors, are essential for all eukaryotic cells. Our laboratory has extensively studied the role of importin-mediated signaling in neuronal length-sensing, as well as in nerve injury response signaling. Going beyond these roles, does importin-mediated transport and importin-dependent signaling impact general physiology, behavior, and pathology? Is long-distance importin-dependent transport necessary for neuronal functions or maintenance? Can modulation of importin functions affect human diseases? These questions require combining analyses at molecular, physiological and behavioral levels, to understand importin roles in integrative physiology.
Importin β1 and memory
Based on importin β1’s role in retrograde injury signaling in the PNS, we tested its potential functions in the CNS. In previous studies, we generated an importin β1 3’UTR deletion (3’UTRKO) mouse line, and demonstrated that this causes subcellular reduction of importin β1 mRNA and protein in axons (Perry et al., 2012). Sensory neurons from the 3’UTRKO line exhibit growth and regeneration phenotypes (Perry et al., 2012, 2016). Behavioral analyses of the 3’UTRKO mouse line revealed spatial memory deficits. The mechanisms underlying this specific effect of importin β1 on memory functions are currently under investigation.
Importin α5 and anxiety
A behavioral screen on a battery of importin α knockout mouse lines revealed significant lack of anxiety in importin α5 knockout mice (Panayotis et al., 2018). This deficit is unique among the importin knockout lines tested. Further analyses suggested that the mechanistic basis for anxiety effects is reduced MeCP2 nuclear import in the hippocampus. MeCP2 is a critical transcription factor in neurons, repressing transcription of sphingosine kinase 1, amongst many other genes. The downstream effect of this pathway perturbation is reduced anxiety. Cross-referencing the transcriptome of importin α5 knockout hippocampi to the CMAP database of drug-induced transcriptomes identified the plant metabolite β-sitosterol as a candidate anxiety reducer (Panayotis et al., 2021). β-sitosterol is on the market as a nutraceutical for other indications, and anecdotal evidence supports its anxiety-reducing effects in humans as well. We are currently examining a number of options for leveraging importin α5 pathways for drug discovery.
Importin α3 and chronic pain
The same importin knockouts behavioral screen revealed significant amelioration in nociception in importin α3 knockout mice (Marvaldi et al., 2020). Strikingly, the phenotype extended to improved recovery from chronic pain in a spared nerve injury model. Biochemical and transcriptomic analyses suggest that the effects are due to reduced nuclear import of cFOS in sensory neurons. We are further investigating this pathway as a potential new target for therapeutic development.
Importins and ALS
A new project in the lab' aims to study connections between importin-dependent mechanisms in axons and the motor neuron disease ALS. Axonal degeneration in ALS begins at the neuromuscular junction, and we postulate that importin-dependent axon-to-soma signaling might be implicated in disease initiation or progression. We are investigating this hypothesis as part of a consortium of four laboratories with complementary expertise in this area. More details will be posted soon.