UC San Diego

The Dual Leucine Zipper Kinase (DLK) is a key molecule involved in various aspects of neuronal development and stress response. Prior studies have identified essential roles in neuron migration, axon formation, synapse formation, regeneration after injury, axon degeneration, and cell death, though neuronal outcomes to stress show clear differences depending on cell type and context. As the DLK signaling pathway is an attractive therapeutic target to modulate regeneration and cell death, this dissertation explores the roles and signaling network of DLK in hippocampal glutamatergic neurons. Examining DLK in this neuron population enhances our understanding of neurodegenerative conditions affecting the hippocampus. In Chapter 1, I provide a detailed introduction to DLK and cell type-specific vulnerabilities, including the known roles and gene networks acting downstream of DLK across various cell types and stress responses in mice. In Chapter 2, I use mouse models of DLK conditional knockout or overexpression in glutamatergic neurons to gain insights into the roles of DLK in hippocampus. Loss of DLK has no effect on hippocampal morphology or microtubules, consistent with the actions of DLK generally having minor effects in absence of stress. In contrast, increasing the level of DLK leads to strong cell type-specific cell death, with dorsal CA1 particularly affected. I further characterize the neuronal translatome in response to DLK loss or elevation to gain insight into the signaling network of DLK in these neurons. The translational targets reveal both conserved and cell-type specific signatures. I also identify STMN4 as a downstream target of DLK endogenously and under conditions of stress. Finally, I characterize changes to microtubules, neuronal outgrowth, and synapses with altered levels of DLK, which may be linked to the regulation of STMN4. Taken together, my work enhances our understanding of DLK’s regulation of neuronal stress responses and its impact on hippocampal neurons, providing insight into neurodegenerative conditions affecting the hippocampus.