Browsing by Author "Shadrach, Jennifer L."

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    DLK signaling in axotomized neurons triggers complement activation and loss of upstream synapses
    (Elsevier, 2024) Asghari Adib, Elham; Shadrach, Jennifer L.; Reilly-Jankowiak, Lauren; Dwivedi, Manish K.; Rogers, Abigail E.; Shahzad, Shameena; Passino, Ryan; Giger, Roman J.; Pierchala, Brian A.; Collins, Catherine A.; Anatomy, Cell Biology and Physiology, School of Medicine
    Axotomized spinal motoneurons (MNs) lose presynaptic inputs following peripheral nerve injury; however, the cellular mechanisms that lead to this form of synapse loss are currently unknown. Here, we delineate a critical role for neuronal kinase dual leucine zipper kinase (DLK)/MAP3K12, which becomes activated in axotomized neurons. Studies with conditional knockout mice indicate that DLK signaling activation in injured MNs triggers the induction of phagocytic microglia and synapse loss. Aspects of the DLK-regulated response include expression of C1q first from the axotomized MN and then later in surrounding microglia, which subsequently phagocytose presynaptic components of upstream synapses. Pharmacological ablation of microglia inhibits the loss of cholinergic C boutons from axotomized MNs. Together, the observations implicate a neuronal mechanism, governed by the DLK, in the induction of inflammation and the removal of synapses.
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    Translatomic analysis of regenerating and degenerating spinal motor neurons in injury and ALS
    (Elsevier, 2021-06-08) Shadrach, Jennifer L.; Stansberry, Wesley M.; Milen, Allison M.; Ives, Rachel E.; Fogarty, Elizabeth A.; Antonellis, Anthony; Pierchala, Brian A.; Anatomy and Cell Biology, School of Medicine
    The neuromuscular junction is a synapse critical for muscle strength and coordinated motor function. Unlike CNS injuries, motor neurons mount robust regenerative responses after peripheral nerve injuries. Conversely, motor neurons selectively degenerate in diseases such as amyotrophic lateral sclerosis (ALS). To assess how these insults affect motor neurons in vivo, we performed ribosomal profiling of mouse motor neurons. Motor neuron-specific transcripts were isolated from spinal cords following sciatic nerve crush, a model of acute injury and regeneration, and in the SOD1G93A ALS model. Of the 267 transcripts upregulated after nerve crush, 38% were also upregulated in SOD1G93A motor neurons. However, most upregulated genes in injured and ALS motor neurons were context specific. Some of the most significantly upregulated transcripts in both paradigms were chemokines such as Ccl2 and Ccl7, suggesting an important role for neuroimmune modulation. Collectively these data will aid in defining pro-regenerative and pro-degenerative mechanisms in motor neurons.