The role of a pair of MAP3Ks in the multicellular response to spinal cord injury

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PROJECT SUMMARY / ABSTRACT After spinal cord injury, a plethora of cellular responses impact functional recovery. Neurons may be preserved or undergo cell death, axon degeneration and/or regenerative attempt. Astrocytes may become hypertrophic, seal off the injury epicenter and influence axonal response in complex ways. Other cell types such as fibroblasts/pericytes, microglia, macrophages also play important roles. Understanding how different cell types respond to injury, how their responses are regulated and how they contribute to functional recovery is critical for developing therapeutic intervention to promote functional repair after spinal cord injury. Regeneration is axonal growth from injured neurons and sprouting is axonal growth from uninjured neurons. Both may contribute to functional recovery. DLK and LZK are mammalian homologues of invertebrate DLK that has been shown to play important roles in axon regeneration in C. elegans and Drosophila. The role of mammalian DLK and LZK in spinal cord repair in not known. In the process of studying DLK (MAP3K12) and LZK (MAP3K13) in axonal repair after spinal cord injury, our lab has identified a critical role for LZK in astrocytic scarring. This result corroborates with published literature on Stat3 and Pten to illustrate an emerging theme that signaling pathways regulating axonal repair may also regulate astrocyte response to injury. In this supplement proposal, we will investigate the astrocyte specific roles of LZK in spinal cord injury and repair using an array of inducible loss and gain of function mouse genetic lines. We will map the interaction of LZK with another known signaling pathway involving Stat3 in regulating astrocyte response, determine the transcriptomic changes and functional consequences of manipulating these pathways. Together, these studies will contribute to the understanding of how the astrocyte response is regulated and how it contributes to repair and recovery in both a direct and indirect manner, the latter through the effect on axonal repair. Such understanding will pave the way for therapeutic development targeting these molecules to promote repair and recovery after spinal cord injury.