DLK-dependent protein network regulates hippocampal glutamatergic neuron degeneration

The conserved MAPKKK DLK plays many roles in neuronal development, axon injury, and neuronal stress responses. The outcomes of activating or inhibiting DLK signaling depend on cell-type and cellular contexts. Emerging evidence has implicated DLK signaling in several neurodegenerative diseases. However, our understanding of the DLK-dependent cellular network in the central nervous system remains limited. Here, we investigated roles of DLK in hippocampal glutamatergic neurons, using conditional knockout and overexpression mice. We find that dorsal CA1 and dentate gyrus neurons are particularly vulnerable to elevated DLK activity. We performed RiboTRAP-seq analysis and identified the DLK dependent translatome, majority of which are involved in neuronal developmental processes, neuronal stress responses, and synapse formation and function. Increasing DLK signaling is associated with disruptions of microtubules, potentially involving Stmn4. We also show that in primary hippocampal neurons DLK regulates neurite outgrowth, axon specification, and synapse formation. This study broadens our understanding of both conserved and cell-type specific effects of DLK signaling. The identification of translational targets of DLK in glutamatergic neurons has relevance to our understanding of neurodegenerative disease. To investigate DLK roles in hippocampal glutamatergic neurons we generated mice with conditional overexpression or conditional knockout of DLK in glutamatergic neurons using Vglut1-Cre mice. Mice were crossed to Ribotag mice and actively translated mRNA from hippocampal glutamatergic neurons from the respective genotypes was sequenced. All samples are from the P15 timepoint. Three or four biological replicates for overexpression or knockout and respective sibling controls were used.