Translatome analysis reveals cellular network in DLK-dependent hippocampal glutamatergic neuron degeneration

Author:

Ritchie Erin M12,Zhong Siming1,Pu Qianyi1,Li Yunbo1,Zheng Binhai3,Jin Yishi134ORCID

Affiliation:

1. Department of Neurobiology, School of Biological Sciences, University of California San Diego

2. Biomedical Sciences Graduate Program, School of Medicine, University of California San Diego

3. Department of Neurosciences, School of Medicine, University of California San Diego

4. Kavli Institute of Brain and Mind, University of California San Diego

Abstract

The conserved MAP3K12/Dual Leucine Zipper Kinase (DLK) plays versatile roles in neuronal development, axon injury and stress responses, and neurodegeneration, depending on cell-type and cellular contexts. Emerging evidence implicates abnormal DLK signaling in several neurodegenerative diseases. However, our understanding of the DLK-dependent gene network in the central nervous system remains limited. Here, we investigated the roles of DLK in hippocampal glutamatergic neurons using conditional knockout and induced overexpression mice. We found that dorsal CA1 and dentate gyrus neurons are vulnerable to elevated expression of DLK, while CA3 neurons appear largely unaffected. We identified the DLK-dependent translatome that includes conserved molecular signatures and displays cell-type specificity. Increasing DLK signaling is associated with disruptions to microtubules, potentially involving STMN4. Additionally, primary cultured hippocampal neurons expressing different levels of DLK show altered neurite outgrowth, axon specification, and synapse formation. The identification of translational targets of DLK in hippocampal glutamatergic neurons has relevance to our understanding of neurodegenerative diseases.

Publisher

eLife Sciences Publications, Ltd

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