The cross-talk between intrinsic and extrinsic mechanism in importin alpha3 mutant DRG neurons

The sensory neurons found in the dorsal root ganglia (DRG) have the remarkable ability to extend up to a meter in length in the adult human body. After injury, axonal regeneration and functional recovery is limited due to the slower growth rate and the mis-targeting, which can cause neuropathic pain (NeuP). Understanding and modulating axonal growth may prevent aberrant regeneration and inaccurate reinnervation of target tissues, dampening NeuP. Previous studies showed that importin α3, a karyopherin protein, plays a role in modulating the chronic NeuP response through its interaction with the transcription factor c-Fos. While importin α3 KO mice showed reduced pain sensitivity, it is unclear if the absence of importin α3 with/without the influence of extrinsic factors such as neurotrophins (i.e., Neurotrophin-3, Nerve Growth Factor) is affecting the neuronal axonal outgrowth and survival after injury. To investigate this, we are exploring: 1) the morphology in vitro of primary sensory neurons in naïve and injury paradigm; 2) the impact of neuronal damage on axonal outgrowth and cell survival in the presence or absence of neurotrophic factors, for which we are employing an in vitro injury model on primary sensory neurons derived from wild-type and importin α3 mutant mice; 3) the genes and pathways that regulate NeuP and axonal growth after injury, by mining through transcriptome datasets and then validating the results via high-throughput imaging and biochemical assays. We aim to provide insights into the molecular mechanisms regulating axonal growth dynamics and pain perception in vivo.