DLK signaling in axotomized neurons triggers complement activation and loss of upstream synapses

Elham Asghari Adib; Jennifer L. Shadrach; Lauren Reilly-Jankowiak; Manish K. Dwivedi; Abigail E. Rogers; Shameena Shahzad; Ryan Passino; Roman J. Giger; Brian A. Pierchala; Catherine A. Collins

Cell Reports (Feb 2024)

DLK signaling in axotomized neurons triggers complement activation and loss of upstream synapses

Elham Asghari Adib,
Jennifer L. Shadrach,
Lauren Reilly-Jankowiak,
Manish K. Dwivedi,
Abigail E. Rogers,
Shameena Shahzad,
Ryan Passino,
Roman J. Giger,
Brian A. Pierchala,
Catherine A. Collins

Affiliations

Elham Asghari Adib: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA; Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA
Jennifer L. Shadrach: Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, USA
Lauren Reilly-Jankowiak: Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA
Manish K. Dwivedi: Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA
Abigail E. Rogers: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
Shameena Shahzad: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
Ryan Passino: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
Roman J. Giger: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
Brian A. Pierchala: Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, MI, USA; Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
Catherine A. Collins: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA; Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 2
p. 113801

Abstract

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Summary: 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.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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